Therapeutic Agent Formulations For Implanted Devices

ABSTRACT

An injectable formulation of therapeutic agent may comprise the therapeutic agent and a stabilizer such that a substantial portion of the stabilizer remains in the therapeutic device to stabilize the therapeutic agent when the therapeutic agent is released from the therapeutic device. The injectable formulation may comprise one or more of binding agent particles or erodible material particles, such that the formulation can be injected into the therapeutic device. The binding agent particles can bind reversibly to the therapeutic agent so as to modulate release of the therapeutic agent, and the erodible material particles can generate protons of an acid so as to increase stability of the therapeutic agent and may modulate release of the therapeutic agent. The therapeutic agent can be combined with one or more of the stabilizer, the binding agent particles or the erodible particles to increase stability of the therapeutic agent and may modulate release.

CROSS-REFERENCES TO RELATED APPLICATIONS

The present PCT application claims priority to U.S. Prov. Pat. App. Ser.No. 61/415,674, filed Nov. 19, 2010, entitled “THERAPEUTIC AGENTFORMULATIONS FOR IMPLANTED DEVICES”, the full disclosure of which isincorporated herein by reference.

STATEMENT AS TO RIGHTS TO INVENTIONS MADE UNDER FEDERALLY SPONSOREDRESEARCH AND DEVELOPMENT

NOT APPLICABLE

BACKGROUND

Described herein are devices and methods of delivery of therapeuticagents to the posterior segment of the eye. Although specific referenceis made to the delivery of macromolecules comprising antibodies orantibody fragments to the posterior segment of the eye, various relatedvariations can be used to deliver many therapeutic agents to manytissues of the body. For example, some variations can be used to delivertherapeutic agent to one or more of the following tissues:intravascular, intra-articular, intrathecal, pericardial, intraluminal,and gut.

The eye is critical for vision. The eye has a cornea and a lens thatform an image on the retina. The image formed on the retina is detectedby rods and cones on the retina. The light detected by the rods andcones of the retina is transmitted to the occipital cortex brain via theoptic nerve, such that the individual can see the image formed on theretina. Visual acuity is related to the density of rods and cones on theretina. The retina comprises a macula that has a high density of cones,such that the user can perceive color images with high visual acuity.

Unfortunately, diseases can affect vision. In some instances the diseaseaffecting vision can cause damage to the retina, even blindness in atleast some instances. One example of a disease that can affect vision isage-related macular degeneration (hereinafter “AMD”). Althoughtherapeutic drugs are known that can be provided to minimize degradationof the retina, in at least some instances the delivery of these drugscan be less than ideal.

In some instances a drug is injected into the eye through the sclera.One promising class of drugs for the treatment of AMD is known asvascular endothelial growth factor (hereinafter “VEGF”) inhibitors.Unfortunately, in at least some instances injection of drugs can bepainful for the patient, involve at least some risk of infection andhemorrhage and retinal detachment, and can be time consuming for thephysician and patient. Consequently, in at least some instances the drugmay be delivered less often than would be ideal, such that at least somepatients may receive less drug than would be ideal in at least someinstances.

Although at least some of the prior proposed implanted devices maypermit an injection of a formulation of therapeutic agent into thedevice, the performance of commercially available formulations oftherapeutic agents can be less than ideal in at least some instanceswhen injected into an implantable device. For example, the commerciallyavailable formulation may have one or more stabilizers having amolecular weight substantially less than the therapeutic agent, suchthat stabilizer may be released from the device at a rate faster thanthe therapeutic agent. Consequently, the therapeutic agent injected intothe device may not receive the benefit of the stabilizer as long aswould be ideal and may degrade more quickly than would be ideal in atleast some instances. Also, the initial rate of release of thetherapeutic agent can be somewhat greater than would be ideal and therate at an extended time can be somewhat lower than would be ideal, suchthat profile of the rate of release can be less than ideal in at leastsome instances.

Work in relation to the various related variations suggests that the pHprovided in situ after injection into a therapeutic device may be lessthan ideal for maintaining stability of the therapeutic agent for anextended time in at least some instances. The stability of thetherapeutic agent can be related to a pH of the formulation within thedevice in at least some instances. For example, deamidation of a proteinbased therapeutic agent may be related to stability of the therapeuticagent, and the deamidation can be related to pH in at least someinstances. Work in relation to variations suggests that priorformulations may provide less than ideal stability in one or more wayswhen injected into a therapeutic device in at least some instances. Forexample, a buffer of the injected formulation may be released from thedevice into the vitreous in at least some instances. Also, diffusion ofhydrogen ions and hydroxide ions between the reservoir and the vitreousmay affect the pH of the formulation within the device.

In at least some instances, one or more molecular components such as abuffer may enter the device when placed in the body, and at least someof the prior formulations may be less stable than would be ideal in atleast some instances when exposed to physiological buffer. For example,a buffer of a fluid of the eye such as the vitreous humor having aphysiological pH may enter the device and affect the pH of theformulation within the device, such that the stability of thetherapeutic agent may be less than ideal in at least some instances.

Work in relation to the various related variations suggests thatinjection of prior formulations of therapeutic agents into a therapeuticdevice may result in at least some aggregation of the therapeutic agentin at least some instances, and the aggregation of therapeutic agent maydecrease stability of the therapeutic agent, such that the stability ofthe therapeutic agent when injected into the therapeutic device withprior formulations can be less than ideal in at least some instances.

In light of the above, it would be desirable to provide improvedformulations of therapeutic agents for therapeutic devices that overcomeat least some of the above deficiencies of the known formulations, forexample with improved drug release that can be maintained over anextended time when implanted.

SUMMARY

Described herein are improved formulations of therapeutic agents andimproved methods and apparatus for placement into therapeutic devicesfor an extended time. A flowable, for example injectable, formulation oftherapeutic agent may comprise the therapeutic agent and a stabilizersuch that a substantial portion of the stabilizer remains in thetherapeutic device so as to stabilize the therapeutic agent when thetherapeutic agent is released from the therapeutic device. Theformulation comprising the therapeutic agent can be placed in thetherapeutic device in many ways, and can be injected into thetherapeutic device, drawn into the therapeutic device with aspiration,or combinations thereof. The injectable formulation may comprise one ormore of binding agent particles or erodible material particles, suchthat the formulation can be injected into the therapeutic device. Thebinding agent particles can bind reversibly to the therapeutic agent soas to modulate release of the therapeutic agent, and the erodiblematerial particles can generate protons of an acid so as to increasestability of the therapeutic agent and may modulate release of thetherapeutic agent. The therapeutic agent can be combined with one ormore of the stabilizer, the binding agent particles or the erodibleparticles, so as to increase stability of the therapeutic agent and maymodulate release of the therapeutic agent from the device.

The stabilizer can interact in many ways with the therapeutic agent soas to increase a stability of the therapeutic agent. The stabilizer maycomprise one or more functional groups so as to form a complex with thetherapeutic agent. The stabilizer may comprise a co-solute with excludedvolume that favors the native state of the protein over the denaturedstate, so as to increase the stability of the protein. The co-solutewith the excluded volume may comprise a stabilizer having a plurality ofhydrophilic functional groups so as to provide the excluded volume tofavor the native state of the protein. The stabilizer may comprise oneor more of a substantially water soluble high molecular weightstabilizer having a molecular weight of at least about 2 k Daltons ormicelles sized so as to correspond to a molecular weight of at leastabout 2 k Daltons. In many variations, the molecular weight of thestabilizer comprises at least about 25% of the molecular weight of thetherapeutic agent, such that a substantial portion of the stabilizerinjected into the chamber of the therapeutic device with the therapeuticagent remains in the chamber of the therapeutic device for an extendedtime when the therapeutic agent is released in therapeutic amountsthrough a porous structure.

The particles of the binding agent may comprise functional groups tobind reversibly to the therapeutic agent such that a substantial portionof the therapeutic agent injected into the chamber of the device may bereversibly bound to the binding agent. The binding agent may compriseporous particles having porous internal channels extending outersurfaces of the particles so as to bind reversibly to the therapeuticagent. The particles may comprise porous resin particles havingderivatized functional groups on surfaces of the inner channels. Thefunctional groups can be located on the outer surface and the surfacesof the inner channels so as to bind reversibly to the therapeutic agent,and the surfaces of the inner channels can be fluidically coupled to theouter surface of the particles such that the therapeutic agent can bereleased from the surfaces of the inner channels. The therapeutic agentreleased from the binding agent can form a complex with the stabilizer,or dissociate from the binding agent into solution, or combinationsthereof. The therapeutic agent bound reversibly to the binding agent,the therapeutic agent complexed with the stabilizer and therapeuticagent in solution can be in substantial equilibrium within the chamberof the device so as to modulate release of the therapeutic agent whenthe therapeutic agent is stabilized.

The particles of erodible material to generate protons of an acid canmaintain a pH of the formulation less than about 7, for example lessthan about 6.5, when injected into the therapeutic device. The pH lessthan about 7 can result in decreased amounts of degradation of thetherapeutic agent that may occur with one or more degradation pathways.The degradation pathway affected with the pH less than 7 can be one ormore of deamidation of the therapeutic agent, such as oxidation of thetherapeutic agent, isomerization of the therapeutic agent, clipping ofthe therapeutic agent, hydrolysis of the therapeutic agent,fragmentation of the therapeutic agent, or aggregation of thetherapeutic agent, or combinations thereof. The particles of erodiblematerial may comprise a polymer, such as polylactic acid (hereinafter“PLA”, polyglutamic acid (hereinafter “PGA”), or combinations thereof,and the particles may generate protons of an acid in response todegradation such as hydrolysis. In many variations, the particles ofbinding agent are pH sensitive so as to bind less with increased pH,such that therapeutic agent can be released from the particles inresponse to an increase in pH.

In a first aspect, variations provide a flowable formulation. Theflowable formulation comprises a therapeutic agent, and a stabilizerhaving a molecular weight of at least about 2 k Daltons.

In many variations, the stabilizer increases an amount of time thetherapeutic agent has a therapeutic effect when placed in a therapeuticdevice placed in a patient. The stabilizer may comprise one or more of,a buffer to maintain a pH of the formulation, hydrophilic functionalgroups, hydrophilic functional group to provide a co-solventstabilization, a charged functional group to provide charge interaction,or a functional group to form a complex with the therapeutic agent, soas to increase one or more of physical stability or chemical stabilityof the therapeutic agent and maintain biological activity of thetherapeutic agent. The stabilizer can be soluble and may comprise one ormore of a sugar, an alcohol, a polyol, or a carbohydrate and wherein thefunctional group comprises a hydroxyl group.

In many variations, the therapeutic agent provides a therapeutic effectwhen placed in the body.

In many variations, the stabilizer comprises a molecular weight of atleast about 3 k Daltons. The stabilizer may comprise a molecular weightof at least about 5 k Daltons, and may comprise a molecular weight of atleast about 10 k Daltons, for example at least about 25 k Daltons.

In many variations, the stabilizer comprises a molecular weight of atleast about 25% of a molecular weight of the therapeutic agent. Thestabilizer and the therapeutic agent may each comprise a half-life whenplaced, for example injected, into a therapeutic device, and thehalf-life of the stabilizer may comprise at least about 25% of thehalf-life of the therapeutic agent. The half-life of the stabilizer maycomprise of at least about 50% of the half-life of the therapeuticagent.

In many variations, the stabilizer is water-soluble and comprises amolecular weight of no more than about 500% of the molecular weight ofthe therapeutic agent.

In many variations, the stabilizer is substantially insoluble in waterand comprises a molecular weight of no more than about 5000% of themolecular weight of the therapeutic agent.

In many variations, the stabilizer comprises a plurality ofsubstantially water insoluble particles. The stabilizer may comprise aplurality of substantially water insoluble particles having hydrophilicfunctional groups and a molecular weight of no more than about 5000% ofthe molecular weight of the therapeutic agent.

In many variations, the therapeutic agent comprises a molecular weightof at least about 40 k. The therapeutic agent may comprise a Fabantibody fragment or a derivative thereof. The therapeutic agentcomprises the Fab antibody fragment and deamidized derivatives of theFab antibody fragment.

In many variations, the therapeutic agent may comprise ranibizumab. Thetherapeutic agent may comprise ranibizumab and degradation products ofranibizumab, and the degradation products may comprise one or more ofdeamidized ranibizumab or oxidized ranibizumab.

In many variations, the stabilizer comprising the molecular weightcomprises one or more of: HA (hyaluronic acid) having the molecularweight of at least 2 k, histidine polymer buffer having the molecularweight of at least 2 k, sugar having the molecular weight of at least 2k, polysaccharides having the molecular weight of at least 2 k,carbohydrate having the molecular weight of at least 2 k, starch havingthe molecular weight of at least 2 k, alcohol having the molecularweight of at least 2 k, polyol having the molecular weight of at least 2k, or polyethylene oxide having the molecular weight of at least 2 k, soas to stabilize the therapeutic agent and decrease release of thetherapeutic agent when placed in a therapeutic device.

In many variations, the stabilizer comprising the molecular weightcomprises one or more of: a phenol, a protein, or a charged stabilizerssuch as a metal comprising one or more of zinc ion, calcium ion, or ironion, so as to form a reversible complex with the therapeutic agent.

In many variations, the stabilizer comprises a plurality of micelles andwherein the molecular weight of the stabilizer corresponds to a weightof each micelle of the plurality such that diffusion of the plurality ofmicelles corresponds to the weight of said each micelle. The pluralityof micelles may comprise a reservoir of the stabilizer. The stabilizermay comprise a surfactant, and a concentration of surfactant comprisesat least about two times a critical micelle concentration of thesurfactant. The concentration of surfactant may comprise at least abouttwo times the critical micelle concentration, and may comprise at leastabout four times the critical micelle concentration.

In many variations, stabilizer comprises a polysorbate.

In many variations, an amount of the stabilizer corresponds to at leastabout 0.05% by weight of the formulation when injected into the eye.

In many variations, said each of the plurality of micelles forms acomplex with the therapeutic agent so as to stabilize the therapeuticagent and decrease diffusion of the therapeutic agent.

In many variations, the container comprises a plurality of particleshaving a dimension across within a range from about 0.1 um across toabout 200 um across, such that the plurality of particles is sized topass through a lumen of a needle. The dimension across can be within arange from about 0.1 um across to about 50 um across, such that theplurality of particles is sized to pass through a lumen of a 33 Gaugeneedle.

In many variations, the container comprises a plurality of pelletshaving a dimension across within a range from about 0.1 um to about 500um, such that the plurality of particles is sized to pass through alumen of a 19 Gauge needle.

In many variations, the plurality of particles comprises one or more ofa plurality of stabilizer particles, a plurality of erodible particlesto generate protons of an acid, or a plurality of binding agentparticles.

In many variations, the container comprises a plurality of binding agentparticles having a dimension across within a range from about 0.1 umacross to about 200 um across, the binding agent particles providing aplurality of reversible binding sites having the therapeutic agentreversibly bound thereon.

In many variations, the therapeutic agent comprises a first portion insolution comprising a first concentration and a second portionreversibly bound to the plurality of binding agent particles comprisinga second concentration. An amount of the second portion of thetherapeutic agent reversibly bound to the plurality of binding agentparticles and a dimension across the plurality of binding agentparticles corresponds to the second concentration of the therapeuticagent. The second concentration can be greater than the firstconcentration.

In many variations, each of the plurality of binding agent particlescomprises internal channels extending therein and wherein the internalchannels comprise the plurality of reversible binding sites. Theplurality of binding agent particles may comprise resin particles havingthe internal channels and an external surface and wherein the internalsurface and the external surface have been treated so as to bindreversibly with the therapeutic agent. The binding agent may comprise asurface derivatized with at least one functional group so as to bindreversibly with the therapeutic agent. The derivatized surface maycomprise an anion exchange surface and wherein the at least onefunctional group comprises one or more of quaternary amines,diethylaminoehtly (hereinafter “DEAE”), quaternary aminoethly(hereinafter “QAE”), or quaternatry ammonidum (hereinafter “Q”). Thederivatized surface comprises a cation exchange surface and wherein theat least one functional group comprises one or more of carboxy methyl(hereinafter “CM”), Sulphoproply (hereinafter “SP”), or methylsulphonate (hereinafter “SP”).

In many variations, the binding agent comprises a negatively chargedsurface within a range of about pH 5.5 to about pH 7.5 so as to bindreversibly to positive charges of the therapeutic agent. The bindingagent comprises a net negative surface charge within a range about pH 6to about pH 7 and wherein the therapeutic agent comprises a net positivecharge so as to bind reversibly to the therapeutic agent. Thetherapeutic agent comprises an isoelectric pH (pI) of at least about 8and wherein binding of the therapeutic agent to the binding agentdecreases substantially when the pH increases from about 6 to about 7.The therapeutic agent comprises at least about ten positive charges andat least about ten negative charges and wherein derivatized surfacecomprises positive and negative charges to bind reversibly to thetherapeutic agent.

In many variations, the at least one functional group increases astability of the therapeutic agent when reversibly bound to thetherapeutic agent.

In many variations, the plurality of binding agent particles have thedimension within the range from about 0.1 um to about 200 um such thatthe plurality of binding agent particles comprises a suspension suitablefor injection into a chamber of a therapeutic device. The range fromabout 0.1 um to about 50 um such that the plurality of binding agentparticles comprises a suspension suitable for injection through a lumenof a 33 Gauge needle. The plurality of binding agent particles may havethe dimension within the range from about 0.5 um to about 100 um suchthat diffusion of the suspension of binding agent particles through aporous structure is substantially inhibited.

In many variations, the plurality of binding agent particles have thedimension across each particle sized greater than a dimension acrosschannels of a porous structure such that passage of the particlesthrough the porous structure is inhibited substantially.

In many variations, the formulation further comprises a plurality ofparticles of an erodible material to release protons of an acid. Theplurality of erodible particles may comprise one or more of a suspensionor a slurry of the erodible particles for injection into or exchangefrom a therapeutic device.

In many variations, the formulation comprises a pH of at least about5.5. The plurality of particles of formulation may be capable ofreleasing about 1E-10 (1×10-10) moles of protons per uL of devicereservoir volume so as to maintain a pH of the formulation below about 7for an extended time of at least about 1 month.

In many variations, the plurality of particles of the erodible materialcomprises an amount corresponding to about 0.01% to about 5% by weightof the formulation. The erodible material a polymer, the polymercomprising one or more of polylactic acid (PLA), polyglutamic acid (PGA)or PLA/PGA copolymer.

In many variations, the formulation further comprises an amount of theerodible material to maintain the pH of the chamber at no more thanabout 6.5 for an extended time of at least about 1 month when injectedinto a chamber of a therapeutic device coupled to the eye with a porousstructure. In many variations, an amount of an erodible material tomaintain the pH of the chamber at no more than about 6.0 for an extendedtime of at least about 1 month when exposed to physiological phosphatebuffer diffused through the porous structure. The amount of an erodiblematerial may be sufficient to maintain the pH of the chamber at no morethan about 6.0 for an extended time of at least about 3 months whenexposed to physiological phosphate buffer diffused through the porousstructure.

In many variations, the plurality of erodible particles comprises aratio of PLA to PGA to erode and release protons at a rate to maintainthe pH.

In many variations, the plurality of erodible particles comprises aportion of the particles covered with a coating to delay erosion of theportion.

In many variations, the plurality of erodible particles comprisesdistribution of sizes so as to erode and release protons at a rate tomaintain the pH.

In many variations, the plurality of particles comprises the stabilizermixed with the erodible material to provide the stabilizer when theparticle erodes.

In an interrelated aspect, variations provide an injectable formulation.The injectable formulation comprises therapeutic agent, and a stabilizercomprising a plurality of micelles.

In many variations, each of the plurality of micelles comprises a weightcorresponding to molecular weight of at least about 2 k Daltons, and theplurality of micelles comprises a reservoir of the stabilizer. A firstportion of the stabilizer comprises a solution of the stabilizer and asecond portion of the stabilizer comprises the micelles and wherein thestabilizer is released from the micelles to the solution maintain aconcentration of the first portion of the stabilizer in solution. Thestabilizer may comprise a polymeric surfactant and wherein aconcentration of polymeric surfactant is higher than a thresholdconcentration to form one or more of the plurality of micelles andwherein the concentration of the polymeric surfactant comprises thefirst portion and the second portion.

In another interrelated aspect, variations provide injectableformulation, the formulation comprises a therapeutic agent, and anerodible material to generate protons of an acid. The erodible materialcomprises an amount to erode and maintain a pH of no more than about 6.5when the formulation is combined with physiological amounts of phosphatebuffer.

In many variations, the injectable formulation further comprises aplurality of particles, wherein each of the plurality of particlescomprises the erodible material and a hydrophilic stabilizer such thatthe hydrophilic stabilizer is released when said each particle of theplurality erodes.

In another interrelated aspect, variations provide method of preparingan injectable formulation, the method comprising: combining atherapeutic agent and a stabilizer.

In many variations, the stabilizer has a molecular weight of at leastabout 2 k Daltons.

In another interrelated aspect, variations provide device to treat aneye. The device comprises a reservoir chamber having a volume sized toreceive an injection of an amount of a formulation of a therapeuticagent, and a porous structure to release therapeutic amounts of thetherapeutic agent for an extended time. A stabilizer is configured tomaintain stability of the therapeutic agent in the reservoir chamber,and the stabilizer comprises a molecular weight of at least about 5 kDaltons such that a portion of the stabilizer remains in the reservoirchamber for the extended time.

In many variations, the stabilizer comprises a molecular weight of atleast about 10 k. The stabilizer may comprise a molecular weight of atleast about 25% of a molecular weight of the therapeutic agent, and themolecular weight can be at least about 40 k. The therapeutic agentcomprises a Fab antibody fragment or a derivative thereof. Thetherapeutic agent may comprise ranibizumab.

In many variations, the stabilizer further comprising an amount of anerodible material to maintain the pH of the chamber at no more thanabout 6.5 for an extended time of at least about 1 month.

In many variations, the stabilizer further comprising an amount of anerodible material to maintain the pH of the chamber at no more thanabout 6.0 for an extended time of at least about 1 month.

In many variations, the stabilizer comprises a plurality of particles tobind reversibly to the therapeutic agent, a majority of the plurality ofparticles having a size greater than channels of the porous structuresuch that the particles remain in the reservoir chamber for the extendedtime.

In another interrelated aspect, variations provide method of treating aneye. A therapeutic device comprising a reservoir chamber and a porousstructure is provided, in which the reservoir chamber has a volume sizedto receive an injection of an amount of a formulation of a therapeuticagent, and the porous structure is configured to release therapeuticamounts of the therapeutic agent for an extended time. A stabilizer andthe therapeutic agent are injected into the reservoir chamber, and thestabilizer maintains stability of the therapeutic agent in the reservoirchamber, the stabilizer comprising a molecular weight of at least about5 k Daltons, and a substantial portion of the stabilizer remains in thereservoir chamber for the extended time.

In another interrelated aspect, variations provide an apparatus to treatan eye. A first container comprises a formulation of a therapeuticagent, the formulation comprising a stabilizer and the therapeuticagent, and a second container comprises an erodible material to releaseprotons of an acid.

In many variations, the second container comprises particles of theerodible material such that the particles form a suspension of theerodible material when mixed with the formulation.

In many variations, the erodible material releases an acid when wet soas to maintain substantially a pH of the formulation when mixed with theformulation and injected into a therapeutic device.

In many variations, the second container comprises a syringe having theerodible material stored therein, and the syringe comprises an exchangesyringe.

In many variations, the second container comprises a cartridge havingthe erodible material stored therein, the cartridge configured to coupleto a syringe having the formulation of the therapeutic agent containedtherein, so as to mix the erodible material with the formulation uponinjection into or exchange with a therapeutic device.

In many variations, the container stores the erodible materialsubstantially without water.

In many variations, the stabilizer comprises a molecular weight of atleast about 5 k Daltons and the therapeutic agent comprises a molecularweight of at least about 25 k Daltons.

In many variations, the container comprises a plurality of binding agentparticles having a dimension across within a range from about 0.1 umacross to about 200 um across, the binding agent particles providing aplurality of reversible binding sites to receive the therapeutic agent.

In many variations, the dimension across is within a range from about0.5 um across to about 100 um across.

In many variations, each of the plurality of binding agent particlescomprises internal channels extending therein and wherein the internalchannels comprise the plurality of reversible binding sites. Theplurality of binding agent particles may comprise resin particles havingthe internal channels and an external surface treated so as to bindreversibly with the therapeutic agent.

In many variations, the plurality of particles comprises a secondstabilizer so as to release the second stabilizer when the erodiblematerial erodes and generates the protons of the acid.

In many variations, the second stabilizer comprises one or more of asugar, an alcohol, a polyol, a polysaccharide, or a carbohydrate.

In many variations, the second stabilizer comprises one or more of abuffer or pH modifier.

In many variations, the second stabilizer comprises hydroxyl groups.

In another interrelated aspect, variations provide a method of preparinga formulation. A formulation of a therapeutic agent can be provided, inwhich the formulation comprises a stabilizer and the therapeutic agent.An erodible material is provided to release protons of an acid, and theformulation is mixed with the erodible material.

In another interrelated aspect, variations provide an injectable andexchangeable formulation to treat an eye. The formulation comprises atherapeutic agent having a molecular weight of at least about 40 kDaltons, and a stabilizer having a molecular weight of at least about 10k Daltons. The stabilizer is capable of forming a complex with thetherapeutic agent to stabilize the therapeutic agent. A first pluralityof binding agent particles has a plurality of sites to bind reversiblythe therapeutic agent. A second plurality of erodible particles togenerate an acid, wherein the first plurality of binding agent particlesand the second plurality of erodible particles comprise a suspensionsuch that the formulation is capable of injection into a therapeuticdevice and exchange from the therapeutic device.

In another interrelated aspect, variations provide method of treating aneye. A formulation is provided, and the formulation comprises atherapeutic agent, a stabilizer, a first plurality of binding agentparticles and a second plurality of erodible particles, the therapeuticagent having a molecular weight of at least about 40 k Daltons. Theformulation is placed in a chamber of a therapeutic device.

In many variations, the stabilizer has a molecular weight of at leastabout 10 k Daltons, and the stabilizer is capable of forming a complexwith the therapeutic agent to stabilize the therapeutic agent. The firstplurality of binding agent particles has a plurality of sites to bindreversibly the therapeutic agent. The second plurality of erodibleparticles generates an acid, and the first plurality of binding agentparticles and the second plurality of erodible particles comprise asuspension such that the formulation is capable of injection into atherapeutic device and exchange from the therapeutic device.

In many variations, placing comprises exchanging the formulation with aportion of a previously placed formulation, in which the portion of thepreviously placed formulation comprises, water, deamidated therapeuticagent, and binding agent particles.

The details of one or more variations of the subject matter describedherein are set forth in the accompanying drawings and the descriptionbelow. Other features and advantages of the subject matter describedherein will be apparent from the description and drawings, and from theclaims.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows an eye suitable for incorporation of variations of thetherapeutic device;

FIG. 1A-1 shows a therapeutic device implanted at least partially withinthe sclera of the eye as in FIG. 1;

FIGS. 1A-1-1 and 1A-1-2 show a therapeutic device implanted under theconjunctiva and extending through the sclera to release a therapeuticagent into vitreous humor of the eye so as to treat the retina, inaccordance with variations described herein;

FIG. 1A-2 shows structures of a therapeutic device configured forplacement in an eye as in FIGS. 1A-1 and 1A-1-1, in accordance withvariations described herein;

FIG. 1A-2-1 shows a therapeutic device loaded into an insertion cannula,in which the device comprises an elongate narrow shape for insertioninto the sclera, and in which the device is configured to expand to asecond elongate wide shape for retention at least partially in thesclera, in accordance with variations described herein;

FIG. 1A-2-2 shows a therapeutic device comprising a reservoir suitablefor loading in a cannula, in accordance with variations describedherein;

FIG. 1B shows a therapeutic device configured for placement in an eye asin FIGS. 1A-1 and 1A-1-1, in accordance with variations describedherein;

FIG. 1C shows a therapeutic device configured for placement in an eye asin FIGS. 1A-1 and 1A-1-1, in accordance with variations describedherein;

FIG. 1C-A shows at least one exit port, according to variationsdescribed herein;

FIG. 1C-B shows a syringe being filled with a formulation 190 comprisingtherapeutic agent 110 and one or more of stabilizer 192, binding agent194 or particles 196, for injection into the therapeutic device, inaccordance with variations described herein;

FIG. 2 shows an access port suitable for incorporation with thetherapeutic device, in accordance with variations described herein;

FIG. 3A shows components of a formulation comprising therapeutic agent,stabilizer corresponding to the therapeutic agent, binding agent anderodible particles, in accordance with variations described herein;

FIG. 3B1 shows a stabilizer as in FIG. 3A, in accordance with variationsdescribed herein;

FIG. 3B2 shows a micelle of a stabilizer as in FIG. 3A, in accordancewith variations described herein;

FIG. 3C shows a binding agent having porous channels as in FIG. 3A, inaccordance with variations described herein;

FIG. 3D shows an erodible material comprising an erodible polymer togenerate a proton of an acid as in FIG. 3A, in accordance withvariations described herein;

FIG. 3E shows reactions and equilibrium corresponding to components todetermine release rates of the formulation as in FIG. 3A when injectedinto a therapeutic device, in accordance with variations describedherein;

FIG. 4A shows released fragments of antibodies, and FIG. 4B showsantibody fragments reversibly bound to a substrate, in accordance withvariations described herein;

FIG. 4C shows net charge of ranibizumab from pH 3 to about pH 13, inaccordance with variations described herein;

FIG. 5A shows a therapeutic device coupled to an injector to inserttherapeutic agent into the device, in accordance with variationsdescribed herein;

FIG. 5A-1 shows a therapeutic device coupled to an injector tosimultaneously inject and remove material from the device, in accordancewith variations described herein;

FIG. 5B shows a therapeutic device comprising a micro loop channel, inaccordance with variations described herein;

FIG. 5C-1 shows a therapeutic device comprising a tortuous channel, inaccordance with variations described herein;

FIG. 5C-2 shows a therapeutic device comprising a coiled channel, inaccordance with variations described herein;

FIG. 5D shows an expandable and contractible structure to retain thetherapeutic agent and an outer rigid casing to couple to the sclera, inaccordance with variations described herein;

FIG. 5E shows a membrane disposed over an exit port of a therapeuticdevice, in accordance with variations described herein;

FIG. 5F shows a therapeutic device comprising a tubular membrane clampedonto the therapeutic device, in accordance with variations describedherein;

FIG. 6A-1 shows a therapeutic device comprising a container having apenetrable barrier disposed on a first end, a porous structure disposedon a second end to release therapeutic agent for an extended period, anda retention structure comprising an extension protruding outward fromthe container to couple to the sclera and the conjunctiva, in accordancewith variations described herein;

FIG. 6A-2 shows a therapeutic device as in FIG. 6A-1 comprising arounded distal end, in accordance with variations described herein;

FIG. 6B shows a rigid porous structure configured for sustained releasewith a device as in FIG. 6A-1, in accordance with variations describedherein;

FIG. 6B-1 shows interconnecting channels extending from a first side toa second side of the porous structure as in FIG. 6B, in accordance withvariations described herein;

FIG. 7 shows a therapeutic device coupled to an injector that removesmaterial from the device and injects therapeutic agent into the device,according to variations described herein;

FIG. 8A shows an apparatus comprising a first container having theformulation of therapeutic agent and the second container comprising asyringe having particles of an erodible material loaded thereon togenerate a proton of an acid when mixed with the formulation, inaccordance with variations described herein;

FIG. 8B shows the first and second containers as in FIG. 8A used toprepare the formulation of therapeutic agent prior to injection, inaccordance with variations described herein;

FIG. 8C shows an apparatus comprising a first container having acommercially available formulation of therapeutic agent and the secondcontainer comprising a syringe having one or more of, a stabilizer, abinding agent comprising porous particles, an erodible material togenerate a proton of an acid, in accordance with variations describedherein;

FIG. 8D shows the first and second containers as in FIG. 8C used toprepare the formulation of therapeutic agent prior to injection, inaccordance with variations described herein; and

FIG. 9 shows calibration curves of fluorescein serially diluted in PBSor PBS containing 100 or 1000 ug/mL BSA, in accordance with variationsdescribed herein.

DETAILED DESCRIPTION

Although specific reference is made to the delivery of macromoleculescomprising antibodies or antibody fragments to the posterior segment ofthe eye, a variety of implementations described herein can be used todeliver many therapeutic agents to many tissues of the body. Forexample, variations described herein can be used to deliver therapeuticagent for an extended period to one or more of the following tissues:intravascular, intra articular, intrathecal, pericardial, intraluminal,and gut.

Various implementations as described herein are suitable for combinationin accordance with U.S. patent application Ser. No. 12/696,678 filed onJan. 29, 2010, entitled “POSTERIOR SEGMENT DRUG DELIVERY,” published onOct. 7, 2010 as U.S. Pub. No. 2010/0255061, the full disclosure of whichis incorporated herein by reference.

Variations described herein provide sustained release of a therapeuticagent to the posterior segment of the eye or the anterior segment of theeye, or combinations thereof. Therapeutic amounts of a therapeutic agentcan be released into the vitreous humor of the eye, such that thetherapeutic agent can be transported by at least one of diffusion orconvection to the retina or other ocular tissue, such as the choroid orciliary body, for therapeutic effect.

The formulations as described herein can be combined with manytherapeutic agents, and may comprise one or more components ofcommercially available formulations. The stabilizers and erodibleparticles as described herein can be combined with commerciallyavailable formulations, for example, so as to decrease degradation ofthe therapeutic agent injected into the device.

The formulations as described herein can be combined in many ways andcan be used with one or more of many therapeutic devices so as toprovide therapeutic amounts for an extended time. The formulation can beprovided within a therapeutic device prior to implantation, and can beplaced in the therapeutic device when the device has been implanted, forexample.

The formulation can be placed in a therapeutic device placed in the eyein many ways. Many variations as described herein are particularly wellsuited for injection into a therapeutic device implanted in the body.Alternatively or in combination, the formulation can be placed in acontainer and the container placed in the therapeutic device implantedin the eye, for example.

As used herein, the release rate index encompasses (PA/FL) where Pcomprises the porosity, A comprises an effective area, F comprises acurve fit parameter corresponding to an effective length and L comprisesa length or thickness of the porous structure. The units of the releaserate index (RRI) comprise units of mm unless indicated otherwise and canbe determined in accordance with the teachings described hereon.

As used herein, sustained release encompasses release of therapeuticamounts of an active ingredient of a therapeutic agent for an extendedperiod of time. The sustained release may encompass first order releaseof the active ingredient, zero order release of the active ingredient,or other kinetics of release such as intermediate to zero order andfirst order, or combinations thereof.

As used herein, a therapeutic agent referred to with a trademarkencompasses the active ingredient available under the trademark andderivatives thereof.

As used herein, similar numerals indicate similar structures and/orsimilar steps.

As used herein, Trehalose encompasses an alpha-linked disaccharideformed by an α,α-1,1-glucoside bond between two α-glucose units.Trehalose can be referred to as mycose or tremalose.

As used herein, the critical micelle concentration (CMC) encompasses theconcentration of surfactants above which micelles are spontaneouslyformed.

As used herein, a surfactant encompasses a wetting agent capable oflowering the surface tension of water.

As used herein, scientific notation of the form a ×10^(−b) can beexpressed as aE-b (or ae-b) with E notation known to persons of ordinaryskill in the art familiar with the use of computer programs, calculatorsand spreadsheets.

The therapeutic agent may be contained within a chamber of a container,for example within a reservoir comprising the container and chamber. Thetherapeutic agent may comprise a formulation such as solution oftherapeutic agent, a suspension of a therapeutic agent or a dispersionof a therapeutic agent, for example. Examples of therapeutic agentssuitable for use in accordance with variations of the therapeutic deviceare described herein, for example with reference to Table 1A below andelsewhere.

Examples of known surfactants suitable for combination with therapeuticagents in accordance with variations as described herein can be found inTable 1B and at one or more locations on the world wide web, such as atthe known website Wikipedia (en.wikipedia.org/wiki/Surfactant). Thesurfactant may comprise an amount sufficient so as to form micellescomprising a reservoir of stabilizer.

The surfactant may comprise a head and a tail. The surfactant may becategorized according to a head of the surfactant and a tail of thesurfactant. The tail may comprise one or more of a hydrocarbon chain, analkyl ether chain, a fluorocarbon chain or a siloxane chain. Thehydrocarbon chain may comprise one or more of aromatic hydrocarbons(arenes), alkanes (alkyl), alkenes, cycloalkanes, or alkyne-basedchains. The alkyl ether chain may comprise one or more of: ethoxylatedsurfactants, such as polyethylene oxides inserted so to increase thehydrophilic character of a surfactant; or propoxylated surfactants:polypropylene oxides inserted to increase the lipophilic character of asurfactant. The fluorocarbon chain may comprise fluorosurfactants. Thesiloxane chain may comprise siloxane surfactants. Surfactant can haveone or two tails (double chained surfactants).

A surfactant may be categorized by the presence of formally chargedgroups in its head. A non-ionic surfactant may have no charge groups inthe head. The head of an ionic surfactant can carry a net charge. Whenthe charge is negative, the surfactant can be more specifically calledanionic. When the charge is positive, the surfactant can be calledcationic. When a surfactant contains a head with two oppositely chargedgroups, the surfactant can be referred to as zwitterionic.

Examples of known polyscahharides that may be combined with thetherapeutic agent in accordance with variations described herein are aslisted in Table 1C, and can be found on the World Wide Web(en.wikipedia.org/wiki/Polysaccharide).

The therapeutic agent may comprise a macromolecule, for example anantibody or antibody fragment. The therapeutic macromolecule maycomprise a VEGF inhibitor, for example the active ingredient ranibizumabof Lucentis™ and derivatives thereof. The VEGF (Vascular EndothelialGrowth Factor) inhibitor can cause regression of the abnormal bloodvessels and improvement of vision when released into the vitreous humorof the eye. Examples of VEGF inhibitors include Lucentis™, Avastin™,Macugen™, and VEGF Trap that can be provided with formulations inaccordance with variations described herein.

The therapeutic agent may comprise small molecules such as of acorticosteroid and analogues thereof. For example, the therapeuticcorticosteroid may comprise one or more of trimacinalone, trimacinaloneacetonide, dexamethasone, dexamethasone acetate, fluocinolone,fluocinolone acetate, or analogues thereof. Alternatively or incombination, the small molecules of therapeutic agent may comprise atyrosine kinase inhibitor comprising one or more of axitinib, bosutinib,cediranib, dasatinib, erlotinib, gefitinib, imatinib, lapatinib,lestaurtinib, nilotinib, semaxanib, sunitinib, toceranib, vandetanib, orvatalanib, for example.

The therapeutic agent may comprise an anti-VEGF therapeutic agent.Anti-VEGF therapies and agents can be used in the treatment of certaincancers and in age-related macular degeneration. Examples of anti-VEGFtherapeutic agents suitable for use in accordance with the variationsdescribed herein include one or more of monoclonal antibodies such asbevacizumab (Avastin™) or antibody derivatives such as ranibizumab(Lucentis™), or small molecules that inhibit the tyrosine kinasesstimulated by VEGF such as lapatinib (Tykerb™), sunitinib (Sutent™),sorafenib (Nexavar™), axitinib, or pazopanib.

The therapeutic agent may comprise a therapeutic agent suitable fortreatment of dry AMD such as one or more of Sirolimus™ (Rapamycin),Copaxone™ (Glatiramer Acetate), Othera™, Complement C5aR blocker,Ciliary Neurotrophic Factor, Fenretinide or Rheopheresis.

The therapeutic agent may comprise a therapeutic agent suitable fortreatment of wet AMD such as one or more of REDD14NP (Quark), Sirolimus™(Rapamycin), ATG003; Regeneron™ (VEGF Trap) or complement inhibitor(POT-4).

The therapeutic agent may comprise a kinase inhibitor such as one ormore of bevacizumab (monoclonal antibody), BIBW 2992 (small moleculetargeting EGFR/Erb2), cetuximab (monoclonal antibody), imatinib (smallmolecule), trastuzumab (monoclonal antibody), gefitinib (smallmolecule), ranibizumab (monoclonal antibody), pegaptanib (smallmolecule), sorafenib (small molecule), dasatinib (small molecule),sunitinib (small molecule), erlotinib (small molecule), nilotinib (smallmolecule), lapatinib (small molecule), panitumumab (monoclonalantibody), vandetanib (small molecule) or E7080 (targetingVEGFR2/VEGFR2, small molecule commercially available from Esai, Co.)

The amount of therapeutic agent within the therapeutic device maycomprise from about 0.01 mg to about 100 mg, for example Lucentis™, soas to provide therapeutic amounts of the therapeutic agent for theextended time, for example at least 30 days. The extended time maycomprise at least 90 days or more, for example at least 180 days or forexample at least 1 year, at least 2 years or at least 3 years or more.The target threshold therapeutic concentration of a therapeutic agentsuch as Lucentis™ in the vitreous may comprise at least a therapeuticconcentration of 0.1 ug/mL. For example the target thresholdconcentration may comprise from about 0.1 ug/mL to about 5 ug/mL for theextended time, where the upper value is based upon calculations shown inExample 9 of U.S. patent application Ser. No. 12/696,678 filed on Jan.29, 2010, entitled “POSTERIOR SEGMENT DRUG DELIVERY,” published on Oct.7, 2010 as U.S. Pub. No. 2010/0255061, the full disclosure of which hasbeen previously incorporated by reference. The target thresholdconcentration is drug dependent and thus may vary for other therapeuticagents.

The delivery profile may be configured in many ways to obtain atherapeutic benefit from the sustained release device. For example, anamount of the therapeutic agent may be inserted into the container atmonthly intervals so as to ensure that the concentration of therapeuticdevice is above a safety protocol or an efficacy protocol for thetherapeutic agent, for example with monthly or less frequent injectionsinto the container. The sustained release can result in an improveddelivery profile and may result in improved results. For example, theconcentration of therapeutic agent may remain consistently above athreshold amount, for example 0.1 ug/mL, for the extended time.

The insertion method may comprise inserting a dose into the container ofthe therapeutic device. For example, a single injection of Lucentis™ maybe injected into the therapeutic device.

The duration of sustained delivery of the therapeutic agent may extendfor twelve weeks or more, for example four to six months from a singleinsertion of therapeutic agent into the device when the device isinserted into the eye of the patient.

The therapeutic agent may be delivered in many ways so as to provide asustained release for the extended time. For example, the therapeuticdevice may comprise a therapeutic agent and a binding agent. The bindingagent may comprise small particles configured to couple releasably orreversibly to the therapeutic agent, such that the therapeutic agent isreleased for the extended time after injection into the vitreous humor.The particles can be sized such that the particles remain in thevitreous humor of the eye for the extended time.

The therapeutic agent may be delivered with a device implanted in theeye. For example, the drug delivery device can be implanted at leastpartially within the sclera of the eye, so as to couple the drugdelivery device to the sclera of the eye for the extended period oftime. The therapeutic device may comprise a drug and a binding agent.The drug and binding agent can be configured to provide the sustainedrelease for the extended time. A membrane or other diffusion barrier ormechanism may be a component of the therapeutic device to release thedrug for the extended time.

The lifetime of the therapeutic device and number of injections can beoptimized for patient treatment. For example, the device may remain inplace for a lifetime of 30 years, for example with AMD patients fromabout 10 to 15 years. For example, the device may be configured for animplantation duration of at least two years, with 8 injections (onceevery three months) for sustained release of the therapeutic agent overthe two year duration. The device may be configured for implantation ofat least 10 years with 40 injections (once every three months) forsustained release of the therapeutic agent.

The therapeutic device can be refilled in many ways. For example, thetherapeutic agent can be refilled into the device in the physician'soffice.

The therapeutic device may comprise many configurations and physicalattributes, for example the physical characteristics of the therapeuticdevice may comprise at least one of a drug delivery device with asuture, positioning and sizing such that vision is not impaired, andbiocompatible material. The device may comprise a reservoir capacityfrom about 0.005 cc to about 0.2 cc, for example from about 0.01 cc toabout 0.1 cc, and a device volume of no more than about 2 cc. Avitrectomy may be performed for device volumes larger than 0.1 cc. Thelength of the device may not interfere with the patient's vision and canbe dependent on the shape of the device, as well as the location of theimplanted device with respect to the eye. The length of the device mayalso depend on the angle in which the device is inserted. For example, alength of the device may comprise from about 4 to 6 mm. Since thediameter of the eye is about 24 mm, a device extending no more thanabout 6 mm from the sclera into the vitreous may have a minimal effecton patient vision.

Variations may comprise many combinations of implanted drug deliverydevices. The therapeutic device may comprise a drug and binding agent.The device may also comprise at least one of a membrane, an opening, adiffusion barrier, a diffusion mechanism so as to release therapeuticamounts of therapeutic agent for the extended time.

FIG. 1 shows an eye 10 suitable for incorporation of the therapeuticdevice. The eye has a cornea 12 and a lens 22 configured to form animage on the retina 26. The cornea can extend to a limbus 14 of the eye,and the limbus can connect to a sclera 24 of the eye. A conjunctiva 16of the eye can be disposed over the sclera. The lens can accommodate tofocus on an object seen by the patient. The eye has an iris 18 that mayexpand and contract in response to light. The eye also comprises achoroid 28 disposed between the sclera 24 and the retina 26. The retinacomprises the macula 32. The eye comprises a pars plana 25, whichcomprises an example of a region of the eye suitable for placement andretention, for example anchoring, of the therapeutic device 100 asdescribed herein. The pars plana region may comprise sclera andconjunctiva disposed between the retina and cornea. The therapeuticdevice can be positioned so as to extend from the pars plana region intothe vitreous humor 30 to release the therapeutic agent. The therapeuticagent can be released into the vitreous humor 30, such that thetherapeutic agent arrives at the retina and choroids for therapeuticeffect on the macula. The vitreous humor of the eye comprises a liquiddisposed between the lens and the retina. The vitreous humor maycomprise convection currents to deliver the therapeutic agent to themacula.

FIG. 1A-1 shows a therapeutic device 100 implanted at least partiallywithin the sclera 24 of the eye 10 as in FIG. 1. The therapeutic devicemay comprise a retention structure, for example a protrusion, to couplethe device to the sclera. The therapeutic device may extend through thesclera into vitreous humor 30, such that the therapeutic device canrelease the therapeutic agent into the vitreous humor.

FIGS. 1A-1-1 and 1A-1-2 shows a therapeutic device 100 implanted underthe conjunctiva 16 and extending through the sclera 24 to release atherapeutic agent 110 into vitreous humor 30 of the eye 10 so as totreat the retina of the eye. The therapeutic device 100 may comprise aretention structure 120 such as a smooth protrusion configured forplacement along the sclera and under the conjunctiva, such that theconjunctiva can cover the therapeutic device and protect the therapeuticdevice 100. When the therapeutic agent 110 is inserted into the device100, the conjunctiva may be lifted away, incised, or punctured with aneedle to access the therapeutic device. The eye may comprise aninsertion of the tendon 27 of the superior rectus muscle to couple thesclera of the eye to the superior rectus muscle. The device 100 may bepositioned in many locations of the pars plana region, for example awayfrom tendon 27 and one or more of posterior to the tendon, under thetendon, or with nasal or temporal placement of the therapeutic device.

While the implant can be positioned in the eye in many ways, work inrelation to variations suggests that placement in the pars plana regioncan release therapeutic agent into the vitreous to treat the retina, forexample therapeutic agent comprising an active ingredient composed oflarge molecules.

Therapeutic agents 110 suitable for use with device 100 includes manytherapeutic agents, for example as listed in Table 1A, herein below. Thetherapeutic agent 110 of device 100 may comprise one or more of anactive ingredient of the therapeutic agent, a formulation of thetherapeutic agent, components of a formulation of the therapeutic agent,a physician prepared formulation of therapeutic agent, or a pharmacistprepared formulation of the therapeutic agent. The therapeutic agent maybe referred to with generic name or a trademark, for example as shown inTable 1A.

The therapeutic device 100 can be implanted in the eye to treat the eyefor as long as is helpful and beneficial to the patient. For example,the device can be implanted for at least about 5 years, such aspermanently for the life of the patient. Alternatively or incombination, the device can be removed when no longer helpful orbeneficial for treatment of the patient.

FIG. 1A-2 shows structures of therapeutic device 100 configured forplacement in an eye as in FIGS. 1A-1, 1A-1-1 and 1A-1-2. The device maycomprise retention structure 120 to couple the device 100 to the sclera,for example a protrusion disposed on a proximal end of the device. Thedevice 100 may comprise a container 130 affixed to the retentionstructure 120. An active ingredient, for example therapeutic agent 110,can be contained within a reservoir 140, for example a chamber 132defined by a container 130 of the device. The container 130 may comprisea porous structure 150 comprising a porous material 152, for example aporous glass frit 154, and a barrier 160 to inhibit release of thetherapeutic agent, for example non-permeable membrane 162. Thenon-permeable membrane 162 may comprise a substantially non-permeablematerial 164. The non-permeable membrane 162 may comprise an opening 166sized to release therapeutic amounts of the therapeutic agent 110 forthe extended time. The porous structure 150 may comprise a thickness150T and pore sizes configured in conjunction with the opening 166 so asto release therapeutic amounts of the therapeutic agent for the extendedtime. The container 130 may comprise reservoir 140 having a chamber witha volume 142 sized to contain a therapeutic quantity of the therapeuticagent 110 for release over the extended time. The device may comprise aneedle stop 170. Proteins in the vitreous humor may enter the device andcompete for adsorption sites on the porous structure and thereby maycontribute to the release of therapeutic agent. The therapeutic agent110 contained in the reservoir 140 can equilibrate with proteins in thevitreous humor, such that the system is driven towards equilibrium andthe therapeutic agent 110 is released in therapeutic amounts.

The non-permeable material such as the non-permeable membrane 162, theporous material 152, the reservoir 140, and the retention structure 120,may comprise many configurations to deliver the therapeutic agent 110.The non-permeable membrane 162 may comprise an annular tube joined by adisc having at least one opening formed thereon to release thetherapeutic agent. The porous material 152 may comprise an annularporous glass frit 154 and a circular end disposed thereon. The reservoir140 may be shape-changing for ease of insertion; i.e., it may assume athin elongated shape during insertion through the sclera and then assumean extended, ballooned shape, once it is filled with therapeutic agent.

The porous structure 150 can be configured in many ways to release thetherapeutic agent in accordance with an intended release profile. Theporous structure may comprise a single hole or a plurality of holesextending through a barrier material such as a rigid plastic or a metal.Alternatively or in combination, the porous structure may comprise aporous structure having a plurality of openings on a first side facingthe reservoir and a plurality of openings on a second side facing thevitreous humor, with a plurality of interconnecting channels disposedtherebetween so as to couple the openings of the first side with theopenings of the second side, for example a sintered rigid material. Theporous structure 150 may comprise one or more of a permeable membrane, asemi-permeable membrane, a material having at least one hole disposedtherein, nano-channels, nano-channels etched in a rigid material, laseretched nano-channels, a capillary channel, a plurality of capillarychannels, one or more tortuous channels, tortuous microchannels,sintered nano-particles, an open cell foam or a hydrogel such as an opencell hydrogel.

FIG. 1A-2-1 shows therapeutic device 100 loaded into an insertioncannula 210 of an insertion apparatus 200, in which the device 100comprises an elongate narrow shape for insertion into the sclera, and inwhich the device is configured to expand to a second elongate wide shapefor retention at least partially in the sclera.

FIG. 1A-2-2 shows a therapeutic device 100 comprising reservoir 140suitable for loading in a cannula, in which the reservoir 140 comprisesan expanded configuration when placed in the eye.

FIG. 1B shows therapeutic device 100 placed in an eye as in FIGS. 1A-1and 1A-1-1. The device comprises retention structure 120 to couple tothe sclera, for example flush with the sclera, and the barrier 160comprises a tube 168. An active ingredient 112 comprising thetherapeutic agent 110 is contained within tube 168 comprisingnon-permeable material 164. A porous structure 150 comprising a porousmaterial 152 is disposed at the distal end of the tube 168 to provide asustained release of the therapeutic agent at therapeutic concentrationsfor the extended period. The non-permeable material 164 may extenddistally around the porous material 152 so as to define an opening tocouple the porous material 152 to the vitreous humor when the device isinserted into the eye.

FIG. 1C shows a therapeutic device configured for placement in an eye asin FIGS. 1A-1 and 1A-1-1. An injectable formulation 190 of therapeuticagent 110 can be placed in therapeutic device 100 prior to placement inthe eye. The formulation 190 can be injectable and may comprisetherapeutic agent 110, a stabilizer 192, a binding agent 194 anderodible particles 196. The formulation 190 comprising stabilizer 192and therapeutic agent 110 may be loaded into device 100 by injectioninto the device through an access port 180. The device 100 may comprisebinding, leak, and barrier functions to deliver the therapeutic agentfor the extended time. The stabilizer 192 and therapeutic agent 110 canbe aspirated to replace the stabilizer and therapeutic agent. Thestabilizer can be at least one of flushed or replaced when at leastmajority of the therapeutic agent has been released, such thatadditional therapeutic agent can be delivered from a second, injectedformulation comprising the stabilizer and the therapeutic agent. Amembrane 195 can be disposed over the periphery of the therapeuticdevice 100. The membrane 195 may comprise methylcellulose, regeneratedcellulose, cellulose acetate, nylon, polycarbonate,poly(tetrafluoroethylene) (PTFE), polyethersulfone, and polyvinylidenedifluoride (PVDF). The therapeutic device may comprise barrier 160shaped such that opening 166 comprises an exit port. The therapeuticagent may be released through at least one of a diffusion mechanism orconvection mechanism. The number, size, and configuration of exit portsmay determine the release rate of the therapeutic agent. The exit portmay comprise a convection port, for example at least one of anosmotically driven convection port or a spring driven convection port.The exit port may also comprise a tubular path to which the therapeuticagent may temporarily attach, and then be released under certainphysical or chemical conditions.

FIG. 1C-A shows at least one exit port 167, the exit port can bedisposed on the device 100 to allow liquid to flow from inside thedevice outward, for example when fluid is injected into an injectionport 182 of the device or when an insert such as a glass frit isinserted into the device. The therapeutic device may comprise an accessport 180 for injection and/or removal, for example a septum.Additionally or in the alternative, when the therapeutic device isrefilled, the contents of the device may be flushed into the vitreous ofthe eye.

The access port 180 may be sized to receive an insert comprising acontainer having the therapeutic agent therein. For example, the porousstructure 150 may comprise a container to contain a formulation 190 ofthe therapeutic agent as described herein, in which the containercomprising porous structure 150 can be removed from the device 100 andreplaced.

FIG. 1C-B shows a syringe being filled with a formulation 190 comprisingtherapeutic agent 110 and one or more of stabilizer 192, binding agent194 or particles 196, for injection into the therapeutic device. Theneedle 189 coupled to syringe 188 of injector 187 can be used to drawformulation 190 comprising therapeutic agent 110, stabilizer 192,binding agent 194 and particles 196 from a container 110C. The container110C may comprise a commercially available container, such as a bottlewith a septum, a single dose container, or a container suitable formixing formulations. A quantity 110V of therapeutic agent 110 can bedrawn into injector 187 for injection into the therapeutic device 100positioned within the eye. The quantity 110V may comprise apredetermined quantity, for example based on the volume of the containerof the therapeutic device 110 and an intended injection into thevitreous humor. For example, the quantity 110V may exceed the volume ofthe reservoir container so as to inject a first portion of quantity 110Vinto the vitreous humor through the therapeutic device and to contain asecond portion of quantity 110V within the reservoir container of thetherapeutic device 110. Container 110C may comprise a formulation 190 ofthe therapeutic agent 110.

The formulation 190 may comprise formulations of therapeutic agent asdescribed herein comprising therapeutic agent 110 and one or more ofstabilizer 192, binding agent 194 or particles 196, for exampletherapeutic agents as described herein and with reference to Table 1A.The formulation 190 may comprise components of a concentrated or dilutedformulation of a commercially available therapeutic agent, for exampleAvastin™. The osmolarity and tonicity of the vitreous humor can bewithin a range from about 290 to about 320 mOsm, for example, and theformulation can be substantially isotonic with one or more fluids of thebody and within a range from about 250 to about 250 mOsm. For example, aformulation of Avastin™ may be diluted so as to comprise a formulationhaving an osmolarity and tonicity substantially similar to theosmolarity and tonicity of the vitreous humor, for example within arange from about 280 to about 340, for example about 300 mOsm. While theinjectable formulation 190 comprising therapeutic agent 110, stabilizer192, binding agent 194 and particles 196 may comprise an osmolarity andtonicity substantially similar to the vitreous humor, the formulation190 may comprise a hyper osmotic solution relative to the vitreous humoror a hypo osmotic solution relative to the vitreous humor. Theformulation and osmolarity of the therapeutic agent can be determinedempirically to provide release of therapeutic agent for an extendedtime.

The formulation 190 may comprise components of a commercially availableformulation such as Avastin™ or Lucentis™ combined with one or more ofthe stabilizer, the erodible particles, the surfactant, or the micellesas described herein, for example.

For example, in the United States, Avastin™ (bevacizumab) is approved asan anticancer drug and in clinical trials are ongoing for AMD. Forcancer, the commercial solution is a pH 6.2 solution for intravenousinfusion. Avastin™ is supplied in 100 mg and 400 mg preservative-free,single-use vials to deliver 4 mL or 16 mL of Avastin™ (25 mg/mL). The100 mg product is formulated in 240 mg α,α-trehalose dihydrate, 23.2 mgsodium phosphate (monobasic, monohydrate), 4.8 mg sodium phosphate(dibasic, anhydrous), 1.6 mg polysorbate 20, and Water for Injection,USP. The 400 mg product is formulated in 960 mg α,α-trehalose dihydrate,92.8 mg sodium phosphate (monobasic, monohydrate), 19.2 mg sodiumphosphate (dibasic, anhydrous), 6.4 mg polysorbate 20, and Water forInjection, USP. The commercial formulations are diluted in 100 mL of0.9% sodium chloride before administration and the amount of thecommercial formulation used varies by patient and indication. Based onthe teachings described herein, formulations of Avastin™ can bedetermined to inject into therapeutic device 100. In Europe, theAvastin™ formulation can be substantially similar to the formulation ofthe United States.

For example, in the United States, there are two forms of Triamcinoloneused in injectable solutions, the acetonide and the hexacetonide. Theacetamide is approved for intravitreal injections in the U.S. Theacetamide is the active ingredient in TRIVARIS (Allergan), 8 mgtriamcinolone acetonide in 0.1 mL (8% suspension) in a vehiclecontaining w/w percents of 2.3% sodium hyaluronate; 0.63% sodiumchloride; 0.3% sodium phosphate, dibasic; 0.04% sodium phosphate,monobasic; and water, pH 7.0 to 7.4 for injection. The acetamide is alsothe active ingredient in Triesence™ (Alcon), a 40 mg/ml suspension.

Osmolarity for these formulations can be determined. The degree ofdissociation of the active ingredient in solution can be determined andused to determine differences of osmolarity from the molarity in theseformulations. For example, considering at least some of the formulationsmay be concentrated (or suspensions), the molarity can differ from theosmolarity.

The formulation of therapeutic agent injected into therapeutic device100 may comprise many known formulations of therapeutic agents modifiedin accordance with variations described herein, and the formulationtherapeutic agent may comprise an osmolarity suitable for release for anextended time from device 100. Table 2 shows examples of osmolarity(Osm) of saline and some of the commercially formulations of Table 1Acan be modified in accordance with the variations described herein.

TABLE 2 Summary of Calculations Description Osm (M) Saline (0.9%) 0.308Phosphate Buffered Saline (PBS) 0.313 Lucentis ™ 0.289 Avastin ™ 0.182Triamcinolone Acetonide (Trivaris-Allergan) 0.342 TriamcinoloneAcetonide (Triessence-Alcon) Isotonic* Triamcinolone Acetonide(Kenalog-Apothecon) Isotonic* *As described in package insert

The vitreous humor of the eye comprises an osmolarity of about 290 mOsmto about 320 mOsm. Formulations of therapeutic agent having anosmolarity from about 280 mOsm to about 340 mOsm are substantiallyisotonic and substantially iso-osmotic with respect to the vitreoushumor of the eye. Although the formulations listed in Table 2 aresubstantially iso-osmotic and isotonic with respect to the vitreous ofthe eye and suitable for injection into the therapeutic device, theformulation of the therapeutic agent injected into the therapeuticdevice can be hypertonic (hyper-osmotic) or hypotonic (hypo-osmotic)with respect to the tonicity and osmolarity of the vitreous. Work inrelation to variations suggests that a hyper-osmotic formulation mayrelease the active ingredient of the therapeutic agent into the vitreoussomewhat faster initially when the solutes of the injected formulationequilibrate with the osmolatiry of the vitreous, and that a hypo-osmoticformulation such as Avastin™ may release the active ingredient of thetherapeutic agent into the vitreous somewhat slower initially when thesolutes of the injected formulation equilibrate with the eye. Theappropriate reservoir chamber volume and porous structure for aformulation of therapeutic agent disposed in the reservoir chamber canbe determined so as to release therapeutic amounts of the therapeuticagent for an extended time and to provide therapeutic concentrations oftherapeutic agent in the vitreous within a range of therapeuticconcentrations that is above the minimum inhibitory concentration forthe extended time.

FIG. 2 shows an access port 180 suitable for incorporation with thetherapeutic device 100. The access port 180 may be combined with thetherapeutic devices described herein. The access port may be disposed ona proximal end of the device. The access port 180 may comprise anopening formed in the retention structure 120 with a penetrable barrier184 comprising a septum 186 disposed thereon. The penetrable barrier canreceive the needle 189 sized to pass the formulation 190 as describedherein. The access port may 180 be configured for placement under theconjunctiva 16 of the patient and above the sclera 24.

FIG. 3A shows components of formulation 190 comprising therapeuticagent, stabilizer 192 corresponding to the therapeutic agent, reversiblebinding agent 194 and erodible material 196. The stabilizer 192 maycomprise at least about 20% of the weight of the therapeutic agent, suchthat diffusion of the stabilizer corresponds at least partially todiffusion of the therapeutic agent. The reversible binding agent 194 maycomprise a plurality of particles of binding agent. The erodiblematerial 196 may comprise a plurality of particles.

The stabilizer 192 can interact with the therapeutic agent 110 in one ormore of many ways so as to decrease degradation of the therapeuticagent. For example, the therapeutic agent 110 may comprise protein suchas a Fab antibody fragment or a derivative thereof, and the stabilizer192 may comprise one or more hydrophilic functional groups 192F thatpromote protein stabilization by a co-solvent effect. Alternatively orin combination, the stabilizer 192 may form a complex 192C with thetherapeutic agent 110.

The stabilizers having the molecular weights as described herein can beparticularly well suited to provide stabilization of the therapeuticagent comprising protein with the co-solvent effect, for exampleco-solvent stabilization of ranibizumab protein. A protein solventeffect as described by Arakawa et al., Adv Drug Delivery Reviews,10(1993) 1-28, can be modified and/or combined in accordance withvariations as described herein. In many variations, there can be adecreased amount of the stabilizing co-solute in the immediate vicinityof the therapeutic agent comprising protein relative to bulk solutionsuch that the therapeutic agent comprising protein is preferentiallyhydrated. For example, the co-solutes can be preferentially excludedfrom contact with the surface of the therapeutic agent comprisingprotein so as to preferentially hydrate the therapeutic agent comprisingprotein. Although the exclusion can be entropically unfavorable, thethermodynamic penalty for exclusion can be even higher for protein inthe denatured state due to the larger exposed surface area of thedenatured protein. The lower penalty for the native versus denaturedtherapeutic agent comprising protein can result in stabilization of thetherapeutic agent comprising protein, for example with the highmolecular weight stabilizers of at least 2 k Daltons as describedherein. Similar stabilization may be provided with micelles comprisingstabilizer having hydrophilic functional groups as described herein, forexample.

The stabilizer 192 may comprise one or more functional groups 192F, forexample one or more hydroxyl groups, so as to form a complex 192C withthe therapeutic agent 110. The dynamics of complex formation anddissociation may be slowed down when the stabilizer has more than onefunctional group interacting with the therapeutic agent at the sametime. Hence, larger molecular weight stabilizers may have multipleinteractions, which may slow the diffusion and depletion of stabilizerpresent in the device reservoir, so as to provide a formulation havingimproved stability.

The binding agent 194 may comprise a plurality of binding sites to bindreversibly the therapeutic agent 110. The reversible binding 194B can bepH sensitive. The binding agent 194 may comprise a plurality of channels194C and an outer surface 194S. The plurality of channels 194C canextend from an opening 1940 of the surface 194S substantially throughthe particle of the binding agent 194. The therapeutic agent 110 can bebound reversibly to an inner surface of channel 194C or outer surface194S. The particle of binding agent 194 may comprise a resin havingderivatized inner and outer surfaces so as to bind reversibly totherapeutic agent 110. The formulation 190 may comprise a plurality ofthe particles of binding agent and may comprise one or more of asuspension or a slurry.

The erodible material 196 may comprise a plurality of particles of theerodible material. The erodible material 196 may comprise an erodiblepolymer such as one or more of PLA, PGA or PLA/PGA copolymer(hereinafter “PLGA”). The polymer can erode with hydrolysis so as toprovide a proton 196H of an acid 196A. The hydrolysis may comprisehydrolysis of ester linkages so as to provide one proton per linkagehydrolyzed.

FIG. 3B1 shows a stabilizer as in FIG. 3A. The stabilizer may compriseone or more of an alcohol, a polyol, a phenol, a carbohydrate, a sugar(sucrose, lactose, and glucose), amino acids (glycine, alanine, andproline), or amines (betaine and trimethylamine N-oxide), for example.The stabilizer may comprise a molecular weight corresponding to thetherapeutic agent, for example at least about 20% of the molecularweight of the therapeutic agent. The molecular weight can be sufficientsuch that a portion of the stabilizer remains in the device 100 when aportion of the therapeutic agent is released so as to stabilize aremaining portion of the therapeutic agent. The stabilizer 192 maycomprise a high molecular weight polymer 192P, for example at leastabout 2 k Daltons. The stabilizer may comprise one or more forms ofcellulose (e.g., carboxymethylcellulose, hydroxyethyl cellulose,hydroxypropyl cellulose, hydroxypropyl methylcellulose,methylcellulose), chitin (e.g., chitosan), other oligosaccharides andpolysaccharides, or polymeric forms of amino acids.

The diffusion constant of the stabilizer can be determined, for examplebased on an estimate of hydrodynamic radius corresponding to the cuberoot of the molecular weight as described herein.

Table ZZZ shows diffusion co-efficients and estimates of devicehalf-life relative to Ranibizumab.

Diffusion relative to Ranibizumab Equiv diameter assumes unit densityand is Diff Coeff the diameter Compound MW Temp C. (cm{circumflex over( )}2/s) per molecule Ranibizumab 48,000 37 1.0E−06 Device Half- EquivEquiv % In device Example mW/ D/ Diff Coeff life relative to volumediameter at TA Compound MW (Ran MW) (Ran D) (cm{circumflex over ( )}2/s)Ranibiz. (nm{circumflex over ( )}3) (nm) Half-life Histidine 156 0.0036.75 6.8E−06 0.15 0.3 0.8 0.9 Trehalose 378 0.008 5.03 5.0E−06 0.20 0.61.1 3.1 500 0.010 4.58 4.6E−06 0.22 0.8 1.2 4.2 1000 0.021 3.63 3.6E−060.28 1.7 1.5 8.1 Polysorbate 20 1227 0.026 3.39 3.4E−06 0.29 2.0 1.6 9.52000 0.042 2.88 2.9E−06 0.35 3.3 1.9 13.5 5000 0.104 2.13 2.1E−06 0.478.3 2.5 22.9 10000 0.208 1.69 1.7E−06 0.59 16.6 3.2 31.1 20000 0.4171.34 1.3E−06 0.75 33.2 4.0 39.5 30,000 0.625 1.17 1.2E−06 0.85 49.8 4.644.5 Ranibizumab 48,000 1.000 1.00 1.0E−06 1.00 79.7 5.3 50.0 50,0001.042 0.99 9.9E−07 1.01 83.0 5.4 50.5 BSA 66,000 1.375 0.90 9.0E−07 1.11109.6 5.9 53.6 100,000 2.083 0.78 7.8E−07 1.28 166.1 6.8 58.1Bevacizumab 149,000 3.104 0.69 6.9E−07 1.46 247.4 7.8 62.2 200,000 4.1670.62 6.2E−07 1.61 332.1 8.6 65.0 500,000 10.417 0.46 4.6E−07 2.18 830.311.7 72.8 1,000,000 20.833 0.36 3.6E−07 2.75 1660.6 14.7 77.7 2,500,00052.083 0.27 2.7E−07 3.73 4151.4 19.9 83.1 3.94E+07 8.E+02 1.1E−011.1E−07 9.4 6.5E+04 50.0 92.9 3.15E+08 7.E+03 5.3E−02 5.3E−08 18.75.2E+05 100 96.4 2.52E+09 5.E+04 2.7E−02 2.7E−08 37.5 4.2E+06 200 98.23.94E+10 8.E+05 1.1E−02 1.1E−08 93.6 6.5E+07 500.0 99.3 3.15E+11 7.E+065.3E−03 5.3E−09 187.3 5.2E+08 1000.0 99.6 2.52E+12 5.E+07 2.7E−032.7E−09 374.6 4.2E+09 2000.0 99.8 3.94E+13 8.E+08 1.1E−03 1.1E−09 936.46.5E+10 5000.0 99.9

Table ZZZ shows that the molecular weight, diffusion co-efficient,equivalent diameter of ranibizumab is about 48 k Daltons, 1.0E-6, and5.3 nm, respectively.

The molecular weight of the stabilizer can be provided in 1 k Daltonincrements from about 1 k Dalton to about 200 k Daltons and provide in aTable having about 200 rows similar to Table ZZZ. The parameters ofTable ZZZ determined such as the half-life in the device, the equivalentvolume, the equivalent diameter, and % in the device at the half-life ofthe therapeutic agent 110. The table may comprise a row for eachmolecular weight in 1 k Dalton increments, and the % of stabilizer inthe device compared with the therapeutic agent 110. The table mayinclude columns for two half-lives of the therapeutic agent, threehalf-lives of the therapeutic agent, four half-lives of the therapeuticagent, and the corresponding percentage of stabilizer remaining in thedevice.

The Percentage at 1, 2, 3, 4 5, and 6 Half-Lives can be Determined.

The molecular weight, diffusion coefficient and equivalent diameter oftrehalose is about 0.4 k Daltons, 5.0E-6, and 1.1 nm, respectively. Therelative molecular weight of trehalose to ranibizumab is about 0.8%, andthe relative half-life of trehalose in device 100 is about 20% ofranibizumab. The relative amount of trehalose remaining in therapeuticdevice 100 at the half-life of ranibizumab is about 3.1%. This decreasedhalf-life of trehalose and amount in the device 100 relative toranibizumab is related to the decreased molecular weight of trehaloserelative to ranibizumab.

A disaccharide such as trehalose can be combined with one or more ofmicelles or polymeric proteins as described herein, so as to associatewith the one or more of the micelles or the polymeric proteins so as todecrease a rate of release of the disaccharide from the reservoirchamber.

The molecular weight, diffusion coefficient and equivalent diameter ofpolysorbate 20 is about 1.2 k Daltons, 3.4E-6, and 1.6 nm, respectively.The relative molecular weight of polysorbate to ranibizumab is about2.6%, and the relative half-life of polysorbate 20 in device 100 isabout 29% of ranibizumab. The relative amount of polysorbate 20remaining in therapeutic device 100 at the half-life of ranibizumab isabout 9.5%. This decreased half-life of polysorbate and amount in thedevice 100 relative to ranibizumab is related to the decreased molecularweight of polysorbate relative to ranibizumab.

The diffusion coefficients of Table ZZZ can be determined based onweight for molecular weights up to about 2.5 M Daltons, and based onsize above about 2.5 M Daltons.

The stabilizer may comprise a molecular weight that is at least about10% of the molecular weight of the therapeutic agent; such that thehalf-life of the stabilizer corresponds to at least about 50% of thehalf-life of the therapeutic agent. For example, a stabilizer 192 with amolecular weight of about 5 k Daltons corresponding to about 10% of themolecular weight of ranibizumab, the relative half life of thestabilizer is about half (0.47) of the half life of ranibizumab. Whenthe half-life of the stabilizer is about half that of the therapeuticagent, about ¼ of the stabilizer may remain in the therapeutic devicefor an extended time corresponding to the half-life of the therapeuticagent. For example, when the half-life of the therapeutic agentranibizumab in the device is about 100 days, about ¼ of a 5 k Daltonmolecular weight stabilizer will remain in the therapeutic device.

The stabilizer may comprise a molecular weight that is at least about20% of the molecular weight of the therapeutic agent, such that the halflife of the stabilizer corresponds to at least about 50% of the halflife of the therapeutic agent. At a time of two half livespost-placement in the therapeutic device, the relative proportion ofstabilizer to therapeutic agent is about 1 to 4. This amount ofstabilizer is sufficient to stabilize the therapeutic agent in manyvariations.

FIG. 3B2 shows a micelle 192M of a stabilizer as in FIG. 3A. Thestabilizer 192 may comprise a micelle 192M of the stabilizer 192. Themicelle 192M may comprise a weight corresponding to a molecular weightof the therapeutic agent, such that a substantial portion of themicelles of the injected formulation remain in the reservoir chamber ofthe therapeutic device when the therapeutic agent is released. Theweight of each micelle may correspond to a molecular weight of at leastabout 10% of the therapeutic agent, for example at least about 20%, suchthat the micelle comprises a size so as to inhibit diffusion of themicelle from the reservoir chamber through the porous structure 150.

The micelle 192M may comprise a reservoir of the stabilizer. Forexample, the stabilizer may comprise a first micelle portion and asecond solution portion. The second solution portion may comprise aportion of the surfactant molecule dissolved as a solute in solution.The second solution portion may correspond to a critical micelleconcentration (hereinafter “CMC”). Above this critical thresholdconcentration, additional surfactant added to the solution may bepresent in the form of micelles. The micelle portion can remainsubstantially within the reservoir chamber based on the size and weightof the micelle as described herein. In many variations, each of themicelles may comprise 50 or more surfactant molecules, in which eachsurfactant molecule comprises a molecular chain. The diffusioncoefficient of a micelle of this size may have a weight andcorresponding diffusion coefficient equal or larger than the therapeuticagent, for example. As individual molecules of the stabilizer insolution diffuse through the porous structure 150, the micelle canrelease stabilizer into solution such that the concentration ofstabilizer in solution remains substantially constant. The micelles maycomprise polymeric surfactants that may comprise a first micelle portionand a second solution portion in equilibrium, such that as the secondportion comprising molecules dissolved in solution diffuses through theporous structure the polymeric surfactant on the micelles is releasedinto solution so as to maintain the concentration of polymericsurfactant in solution.

The surfactant may comprise one or more of polysorbates (for example,polysorbate 20 and polysorbate 80, also known as Tween 20 and Tween 80),block copolymers of ethylene oxide or propylene oxide of various sizesmarketed by BASF as Pluronic®, or ethoxylated emulsifiers marketed byBASF as Cremophor®, and combinations thereof.

The surfactant may increase the stability of the therapeutic agent byoccupying interfaces so as to displace therapeutic agent comprisingprotein from the interfaces. The interface may comprise an inner surfaceof the reservoir chamber exposed to the formulation such that the innersurface may interact with the protein, for example an inner surfacehousing or a surface of the porous structure 150. Proteins may undergoconformational changes at interfaces that may then lead to degradationvia any of a number of pathways such as aggregation, deamidation,oxidation, etc. The surfactant may compete with and displace protein atair-liquid interfaces such as at the surface of a bubble or liquid-solidinterfaces such as with displacement of the protein at the exposedsurface inside a porous structure within the device. High concentrationsof surfactant, near or beyond the CMC may be helpful so as tosubstantially displace protein from interfaces and inhibit interactionof the protein with the inner surfaces of device 100. In manyvariations, the surfactant concentration within the reservoir chamber ofthe device can be maintained near or above the CMC for an extended timeas described herein.

The CMC can be determined from a variety of techniques such asmeasurements of surface tension using a Wilhelmy plate. The CMC for aparticular surfactant may be dependent on a variety of parameters suchas the concentrations of other components in the formulation and thetemperature. Values ranging from 1E-5 to 8E-5 are reported in theliterature for polysorbate 20.

Table K1 shows amounts of polysorbate 20 sufficient to maintain thepresence of micelles in representative devices for an extended time ofat least about 6 months, such that the concentration of surfactantstabilizer in device 100 is at least about the CMC of the surfactantstabilizer comprising Polysorbate 20. The diffusion coefficients of3.4E-6 and 8.8E-7 cm2/s for the single molecule (corresponding to thesecond portion) and the micelle (corresponding to the micelle portion),respectively, are obtained based upon molecular weight of 1227 forpolysorbate 20 and assuming a plurality of approximately 50 molecules ofpolysorbate 20 per micelle, in which each of the 50 molecules comprisesa molecular chain such as a polymeric chain. The corresponding particleweight of the micelle comprising the plurality of 50 polysorbate 20molecules can be about 61,350, so as to correspond to a diffusioncoefficient about 3.86 lower than Polysorbate 20, based on the cube rootof the weight of the micelle particle relative to the weight of theindividual Polysorbate 20 molecule (cube root of 50 is about 3.86). Theexamples show polysorbate 20 concentrations 6 or more times larger thanthe CMC can be sufficient so as to maintain micelles in the device atleast about 6 months after placement of the therapeutic agent andmicelles in device 100. In many variations, concentrations of at leastabout 0.04% may be sufficient so as to maintain concentration ofmicelles above the CMC.

TABLE K1 Minimum concentration of polysorbate 20 sufficient to maintainmicelles in device 100, as a function of CMC and device parameters. CMC(M) 1e−5 8e−5 1e−5 8e−5 CMC (wt %) 0.001%  0.01% 0.001%  0.01% DeviceRRI (mm) 0.02 0.02 0.06 0.02 Device Volume (uL) 25 25 25 100 MinimalConc. to 0.005% 0.042% 0.016% 0.042% replenish single chain diffusion(wt %) Half-life of 100 100 30 400 Therapeutic Agent Ranibizumab (days)Minimal Conc. 0.004% 0.029% 0.033% 0.013% corresponding to micellediffusion (wt %) Total Minimal Conc. 0.009% 0.071% 0.048% 0.054% (wt %)Ratio of Total Minimal 7 7 40 6 Conc. to CMC

Table K1 shows that substantial amounts of surfactant can be providedfor an extended time of at least about 6 months so as to stabilize thetherapeutic agent within device 100. In many variations, ranibizumab canbe delivered in therapeutic amounts for an extended time of at leastabout 6 months when therapeutic device 100 comprises a half-life of atleast about 90 days or more, for example.

The amount of surfactant in device 100 can be combined with an amount ofone or more of many therapeutic agents 110 as described herein. The halflife of the therapeutic agent may correspond to the amount of surfactantsufficient to maintain the concentration of surfactant above the CMC.

The amount of surfactant to provide for an intended extended time can bedetermined empirically. For example, the above table shows amounts ofsurfactant sufficient to provide surfactant above the CMC for 6 months.Similar tables for a target intended time of 12 months, for example, canbe determined.

Alternatively or in combination, amounts of surfactant can be determinedto provide concentrations above the CMC for an intended extended time.For example, to achieve a surfactant concentration above the CMC for anextended time of about one year, the minimal concentration correspondingto micelle diffusion can be increased by about 4× when the intended timeis increased by about 2×, so as to provide micelles within device 100for at least about 1 year, for example. With device 100 having areservoir chamber volume of 100 uL and an RRI of about 0.02, to achievemicelles for at least about one year with a CMC of 0.01%, theconcentration of Polysorbate 20 corresponding to micelle diffusion canbe increased from about 0.013% to about 0.017%, and the concentration ofPolysorbate 20 corresponding to individual surfactant molecule diffusioncan be increased from about 0.04% to about 0.08%, such that the totalconcentration of Polysorbate 20 comprises about 0.1%.

The micelle 192M may form a complex 192C with the therapeutic agent 110.Alternatively or in combination, the chains of individual molecules mayassociate with the therapeutic agent, for example form a complex withthe therapeutic agent.

FIG. 3C shows a particle of a binding agent having porous channels as inFIG. 3A. The particle may comprise a plurality of channels and aplurality of openings sized to allow the therapeutic agent 110 todiffuse along the channel 194C and out opening 1940. The porous channelsmay comprise the derivatized surface as described herein.

FIG. 3D shows an erodible material comprising an erodible polymer togenerate a proton of an acid as in FIG. 3A. The polymer may comprise oneor more of polylactic acid 196LA or polyglyoclic acid 196GA, orcombinations thereof, for example. The polymer may comprise manybiodegradable erodible materials, such as polycaprolactone, for example.The particle may comprise a substantial polymer chain 196P, such thatthe particle is sized so as to inhibit diffusion of the particle throughthe porous structure to release the proton of the acid within thereservoir chamber of the therapeutic device 100.

The proton generation based on erodible material such as biodegradablepolymers comprising PLGA can be provided in many ways. In manyvariations, therapeutic agent is located in the fluid surrounding theerodible particles, and may not be encapsulated inside of the particlessuch that the protons released from the particle can be diluted with thefluid surrounding the erodible particle.

The rate of proton generation can be determined by the composition ofthe particles. Variables capable of modulating the degradation of PLGAcan include one or more of a ratio of PLA to PGA, molecular weight,crystallinity, particle size, porosity, and pore size distributions,shape, and processing conditions. For example, increasing the ratio ofPLA to PGA can decrease the rate of degradation, and decreasing theratio of PLA to PGA can increase the rate of degradation. Providingparticles with lower porosity may reduce the fraction of water filledpores and can result in a lower erosion rate. Increasing molecularweight, crystallinity, and particle size may decrease degradation ratesand the rate of proton production.

PLGA particles prepared for encapsulation and delivery of drugs mayachieve drug release for extended periods on the order of weeks ormonths. However, water-soluble drug can be substantially depleted fromPLGA particles before the polymer is completely degraded. Hence, protonsmay be supplied from erosion of PLGA for several months beyond the timesustained drug delivery is achieved. Furthermore, PLGA intended asproton generators can have lower porosity during the erosion process ifthey do not have additional pores forming from depletion of encapsulateddrug. Hence, biodegradable particles for proton generation may beprepared where protons are generated for periods of a year or longer.

The erodible particles may be coated with an excipient that dissolvesslowly in water, so as to delay the time when the biodegradable materialis hydrated and so as to delay the corresponding erosion process. Theerodible particles may comprise enteric coatings. The enteric coatingscan remain intact at slightly acidic conditions and dissolve when pH isincreased toward physiological pH, such that proton generation can bestarted at a time post injection when pH has risen above a targetedthreshold. The time profile of the release of the protons of the acidcan be determined based on a mixture of the particles. For example, thetime profile of proton generation may be modulated by using a mixture ofparticles with varying properties, for example, varying particle size orthickness of the enteric coating.

Coatings with slow dissolution may comprise polymers with limitedsolubility in water, such as ethylcellulose, and may be mixed withpolymers (e.g., hydroxyethylcellulose, sodium carboxymethylcellulose,methyl hydroxyethylcellulose) that are soluble in water to achieve thedesired dissolution profile. The coatings may also comprise polymerswith lower critical solution temperatures, such as methylcellulose,hydroxypropyl cellulose, and hydroxypropyl methylcellulose, that areinsoluble at high temperature and have dramatically increased solubilityin cold water. The desired dissolution profile may be achieved byselection of molecular weights (e.g., increase in molecular weightdecreases solubility and dissolution rate) and by mixing with othersoluble and insoluble polymers and excipients.

Commonly used enteric coating polymers are shown in Table XX. These maybe combined with the coatings above.

TABLE XX Enteric Coating Polymers Polymer Solubility Profile ShellacAbove pH 7 Cellulose acetate phthalate (CAP) Above pH 6 Polyvinylacetatephthalate (PVAP) Above pH 5 Hydroxypropyl methylcellulose phthalate(HPMCP) Above pH 4.5 Polymers of methacrylic acid and its esters AbovepH 6

The above polymers used as coatings may also serve as a proteinstabilizer once dissolved into the solution inside the device. Thesecoatings may stabilize the therapeutic agent by forming a complex withthe therapeutic agent or may stabilize by acting as a co-solute.

Stabilizers larger than 2 kDa may have sufficiently limited solubilityto be present as a suspension in the formulation (e.g., ethylcellulose,methylcellulose, hydroxypropyl cellulose, and hydroxypropyl methylcellulose). For example, small particles of these polymers could beprepared by micronization and milling, or by emulsion or spray dryingtechniques.

Coatings that delay dissolution, whether pH triggered or not, may alsobe used with other solid reservoirs of stabilizers that replenishstabilizer as it is depleted and delivered to the vitreous. For example,micronized trehalose could be coated for delayed dissolution.

The erodible material to generate the proton of the acid and stabilizersto decrease degradation of the therapeutic agent can be combined in manyways. For example, formulation stabilizers, such as buffers and sugars,may be encapsulated in biodegradable particles so as to release a secondportion of stabilizer that replenishes a first portion stabilizer thathas been released into the vitreous. For example, as trehalose is stableat acidic conditions, the erodible particles may comprise trehalosestabilizer and the erodible material. Alternatively or in combination,the erodible particles may comprise buffer so as to release the bufferwith erosion of the particles. The buffer may comprise one or morebuffers including, for example, acetate, succinate, gluconate,histidine, citrate, and organic acid buffers. The stabilizer may alsocomprise pH modulators such as chloride salts.

Table Z1 to Table Z5 shows amounts of PLGA polymer to provide a pH ofabout 5.5 for an extended time of at least about 1 year. These tablesinclude calculations for the flux of protons out of the device 100, andalso calculations of physiological phosphate into the device, so as todetermine amounts of erodible polymer based on diffusion of vitreousbuffer into device 100.

TABLE Z1 Molecular weights of PGA, PLA and PLGA MW of repeat unit PGA 58PLA 76 Ave. 67

As shown in Table Z1, PGA and PLA have molecular weights of 58 and 76respectively, with an average of about 67 k Daltons. These molecularweights correspond to about 67 mg per mmole of PLGA.

TABLE Z2 Phosphate pKa's and concentrations in the vitreous humor.Phosphate pKa2 7.21 Ka2 6.17E−08 Phosphate (M) 0.01

Table Z2 shows the pKa2 of phosphate to be about 7.21, and the Ka2 to beabout 6.17E08. The molarity of the phosphate buffer is about 0.1, whichcorresponds to the vitreous humor and many bodily fluids, for exampleblood. After an amount of time within a range from about two weeks toabout three months, a formulation with a small molecular weight buffer(e.g., histidine) may be depleted in the reservoir of the device. Atthat time, the reservoir may be in substantial equilibrium with thebuffers in the vitreous (e.g., phosphate) and comprise physiologicalconcentrations of the vitreous buffers.

TABLE Z3 The change of H2PO4 concentration and corresponding pH's pH[H+] pOH [OH−] HPO4/H2PO4 H2PO4 (M) HPO4 (M) Extra H+ (M) 5.5 3.16E−068.5 3.16E−09 0.02 0.00981 0.00019 0.0059 7.4 3.98E−08 6.6 2.51E−07 1.550.00392 0.00608

The pH within the device can be about 5.5, and the pH of the vitreoushumor can be about 7.4. Addition of phosphate into a device at pH 5.5may change the pH of the device unless additional protons are provided.Table Z3 shows information on the concentrations of phosphate species atthe vitreous and device pH values, to enable calculation of the amountof protons required to maintain pH in the device in the presence of 0.1M phosphate. The corresponding [H+], pOH, and [OH—] values are shown.The ratio of [HPO₄ ²⁻] to [H₂PO₄ ⁻] is shown to be 0.02 and 1.55 for pH5.5 and 7.5, respectively. The corresponding molarities (M) of H₂PO₄ ⁻,HPO₄ ²⁻, and extra proton to decrease the pH are shown.

TABLE Z3 RRI, reservoir volume and density RRI (mm) 0.02 Reservoir vol(uL) 25 Density of PLGA (mg/uL) 1

Table Z3 shows an example of a device having an RRI of 0.02 andreservoir volume of 25 uL. The density of PLGA is about 1 mg/ul.

The half-life of Lucentis™ in device 100 having the RRI of 0.02 andreservoir volume of 25 uL is about 100 days, as described in U.S. Pub.No. 2010/0255061, the full disclosure of which has been previouslyincorporated by reference and suitable for combination in accordancewith variations described herein.

TABLE Z4 PLGA to preplace H+ that diffuses across the porous structure150, also referred to as rate control element (hereinafter “RCE”). PLGAto replace H+ that diffuses out across RCE H+ OH− Diffusion Coeff(cm{circumflex over ( )}2/s) 9.31E−05 5.28E−05 Source: Cussler, E. L.,“Diffusion”, Cambridge University Press, first edition, 1984, pg 147Conc in Reservoir (M) 3.16E−06 3.16E−09 Conc in Receiver (M) 3.98E−082.51E−07 Conc Change across RCE 3.12E−06 −2.48E−07 (M) Rate (mmole/day)5.02E−08 −2.26E−09 Assume amount of OH− transported is negligiblecompared to H+ Rate (mmole/month) 1.51E−06 Rate (mmole/year) 1.83E−05−8.26E−07 Rate (ug PLGA/year) 1.23 Rate (uL PLGA/year) 1.23E−03 Volumefraction 0.005%

Table Z4 shows that erosion of about 1.23E-03 ug of PLGA per yearcorresponds to the diffusion of H+ ions across porous structure 150. Thecorresponding volume fraction is about 0.005% of the 25 uL volume. Thediffusion coefficient of H+ proton ions in solution is about 9.31E-05.

Table Z5 shows PLGA to protonate phosphate that diffuses into device 100across porous structure 150 from a bodily fluid such as the vitreoushumor.

PLGA required to protonate phosphate (change of pH from 7.4 to 5.5 orvalue set above). Assumes all histidine buffer has diffused out of thedevice and device now contains phosphate at concentrations inequilibrium with the vitreous (0.01M) H+ Extra H+ (M) 0.0059 Extra H+1.47E−04 Concentration converted to amount based (mmole) upon reservoirvolume PLGA (ug) 9.86 PLGA (uL) 9.86E−03 Volume fraction 0.039%

Table Z5 shows that the extra H+ to be protonated corresponds to about0.0059 M based on Table Z3 above. The amount of PLGA per yearcorresponds to about 9.86 ug having a volume of about 9.86 uL. For the25 uL device, this corresponds to about 0.039% of the device.

Tables Z1 to Z5 show amounts of erodible material in accordance withmany variations. One or more of the following may be adjusted inaccordance with the variations described herein: target pH within device100, volume of device 100, release rate of porous structure 150,half-life of therapeutic agent in device 100, rate of erosion of theerodible material comprising PLGA.

FIG. 3E shows reactions and equilibrium corresponding to components todetermine release rates of the formulation as in FIG. 3A when injectedinto a therapeutic device. The stabilizer 192 and therapeutic agent 110can be in equilibrium with complex 192C having a correspondingequilibrium constant Ks. The binding agent 194 and therapeutic agent 110can be in pH dependent equilibrium with reversible binding 194B oftherapeutic agent and binding agent corresponding to pH dependentequilibrium constant Kb. The erodible polymer can generate protons of anacid 196A with hydrolysis corresponding to equilibrium constant. Thecorresponding concentrations of therapeutic agent 110, complex 192C ofstabilizer 192 and therapeutic agent 110 and protons H+ can be used todetermine the diffusive flux of each of these components through porousstructure 150 so as to determine the profile of the rate of release oftherapeutic agent 110.

The release of therapeutic agent 110 may be modulated by one or more ofthe pH or the concentration of stabilizer 192 within the reservoirchamber. The increase in pH from about 6.5 to about 7 can shift theequilibrium of the binding agent and therapeutic agent towarddissociated therapeutic agent so as to increase the rate of release ofthe therapeutic agent. The decreased amount of stabilizer can shift theequilibrium of stabilizer and therapeutic agent away from complexedtherapeutic agent and toward dissociated therapeutic agent in solution,so as to increase the rate of release of the therapeutic agent.

FIG. 4A shows released antibodies comprising antibody fragments 410 anda substrate 420 comprising binding agent 194, and FIG. 4B shows antibodyfragments 410 reversibly bound to a substrate 420 with binding agent194, in accordance with variations described herein. The anti-bodyfragments can be reversibly bound to the substrate comprising thebinding agent, such that the bound antibody fragments are in equilibriumwith the unbound antibody fragments. Many substrates comprising bindingagent can reversibly bind at least a portion of an antibody. Examples ofbinding media may include particulates used in chromatography, such as:Macro-Prep t-Butyl HIC Support, Macro-Prep DEAE Support, CHT Ceramic,Hydroxyapatite Type I, Macro-Prep CM Support, Macro-Prep Methyl HICSupport, Macro-Prep Ceramic Hydroxyapatite Type II, UNOsphere S CationExchange Support, UNOsphere Q Strong Anion Exchange Support, Macro-PrepHigh-S Support, and Macro-Prep High-Q Support. Additional media to testfor binding include ion exchange and bioaffinity chromatography mediabased on a hydrophilic polymeric support (GE Healthcare) that bindproteins with high capacity, and a hydrophilic packing material fromHarvard Apparatus made from poly(vinyl alcohol) that binds more proteinthan silica. It should be appreciated that other candidates areconsidered herein.

The resin of the plurality of binding particles may comprise one or moreof polystyrene or divinyl benzene. The particles may comprise sphericalparticles and may comprise a plurality of channels. When the reservoirchamber of the therapeutic device corresponds to a net negative chargeof the therapeutic agent, the derivatized surface may comprise an anionexchange surface such as one or more of diethylaminoehtly (DEAE),Quaternary aminoethly (QAE), or quaternatry ammonidum (Q), for example.When the reservoir chamber of the therapeutic device corresponds to anet positive charge of the therapeutic agent, the derivitized surfacemay comprise a cation exchange surface such as one or more of carboxymethyl (CM), Sulphoproply (SP), or methyl sulphonate (SP), for example.

FIG. 4C shows net charge of ranibizumab from pH 3 to about pH 13.Similar plots can be determined for many proteins based therapeuticagents such as Fab antibody fragments and derivatives thereof, such asranibizumab and derivatives thereof. The charge of the therapeutic agentcan be used to determine reversible binding of the therapeutic agent tothe binding agent. In many variations, the therapeutic agent comprisinga protein such as ranibizumab may comprise an improved stability whenthe pH in the reservoir chamber of device is at least about 2 pH unitsfrom the isoelectric point.

TABLE YYY Charge of ranibizumab as a function of pH. Charge 45 10 2 1−50 −60 pH 3 5 7 9 11.5 13

Table YYY shows the charge of the ranibizumab molecule as a function ofpH. The isoelectric point is around pH 9. The charge at pH 5 can beabout +10, and the charge at pH 7 can be about +2, such that the amountof ranibizumab reversibly bound to the binding agent may changesubstantially from about pH 5 to about pH 7. Based on interpolation, thecharge at about pH 6 is about 6. The change in charge from pH 6 to pH 7is about 4, which can provide substantial change in binding so as tomodulate the release of the therapeutic with pH.

Near the isoelectric the total number of negative and positive chargescan be substantial, for example about 36 positive and 35 negativecharges, such that there can be many charges to couple to the bindingagent reversibly. The reversible binding agent may comprise a pluralityof functional groups having both positive and negative charges to bindreversibly with the therapeutic agent. The composition of the buffer maybe modulated, for example with salt so as to shield at least some of thecharge interactions, so as to modulate the ratio of the portion oftherapeutic agent bound to the binding agent to the unbound portion ofthe therapeutic agent, for example.

FIG. 5A shows therapeutic device 100 coupled to injector 187 to inserttherapeutic agent 110 into container 130 of the device. The injector 187may comprise needle 189 coupled to a syringe 188.

FIG. 5A-1 shows a therapeutic device 100 coupled to an injector 187 toinject and remove material from the device. The injector may compriseneedle 189 having a first lumen 189A and a second lumen 189B configuredto insert into a container of the device. The injector maysimultaneously inject 510 therapeutic agent into and withdraw 520 liquidfrom the device. The injector may comprise a first one way valve and asecond one way valve coupled to the first lumen and the second lumen,respectively.

FIG. 5B shows a therapeutic device comprising a microloop channel 530.The microloop channel may extend to a first port 530A and a second port530B, such that the therapeutic agent can be injected into the firstport, for example with a binding agent, and flowable material, forexample liquid comprising binding agent, can be drawn from the microloopchannel 530.

FIG. 5C-1 shows therapeutic device 100 comprising a tortuous channel540. The tortuous channel may comprise extend from a first port 540A toa second port 540B, such that the therapeutic agent can be injected intothe first port and flowable material, for example liquid comprising thebinding agent, can be drawn from the second channel.

FIG. 5C-2 shows a therapeutic device comprising a tortuous coiledchannel 550. The coiled channel 550 can extend to an exit port 552. Aneedle 189 can be inserted into the access port 180 to injecttherapeutic agent into device 100.

FIG. 5D shows an expandable and contactable structure 562 to retain thetherapeutic agent and an outer rigid casing 560 to couple to the sclera.The expandable structure 562 may comprise a membrane, such as at leastone of a bag, a balloon, a flexible reservoir, a diaphragm, or a bag.The outer rigid casing may extend substantially around the structure 562and may comprise an opening to release liquid into the vitreous humorwhen the structure is expanded.

FIG. 5E shows a membrane 565 disposed over an exit port 552 oftherapeutic device 100.

FIG. 5F shows therapeutic device 100 comprising a tubular membrane 572clamped onto the therapeutic device over side ports 570 of device 100.

When the protective membranes have pores of 0.2 um diameter, they are 20or more times larger than the proteins of interest, which may comprise amodel for delivery of the therapeutic agent. For example, molecularweights and diameters of models of proteins of therapeutic interest are:

(a) IgG 150 kDa  10.5 nm (b) BSA 69 kDa  7.2 nm (c) Fab fragment of IgG49 kDa hydrodynamic diameter not reported

Therefore, solutions of therapeutic compounds in the size range of IgGand BSA should flow relatively easily through 0.2 um pore sizeprotective membranes used to stop passage of bacterial and other cells.

Binding Materials/Agents may comprise at least one of a chemical bindingagent/material, a structural binding agent or material, or anelectrostatic binding agent or material. The types of binding agent maycomprise a classification composed of non-biodegradable material, forexample glass beads, glass wool or a glass rod. A surface can bederivatized with at least one functional group so as to impart thebinding agent or material with the potential for at least one of ionic,hydrophobic, or bioaffinity binding to at least one therapeuticcompound.

The binding agent may comprise a biodegradable material. For example,the biodegradation, binding, or a combination of the previous processesmay control the diffusion rate.

The binding agent may comprise ion exchange, and the ion exchange maycomprise at least one of a functional group, a pH sensitive binding or apositive or negative charge. For example, ion exchange can be performedwith at least one of diethylaminoethyl or carboxymethyl functionalgroups.

The binding agent may comprise a pH sensitive binding agent. Forexample, the binding agent can be configured to elute therapeutic agentat a pH of 7, and to bind the therapeutic agent at a pH from about 4 toabout 6.5. A cation exchange binding agent can be configured, forexample, such that at a pH of 7, the net negative charge of the bindingagent decreases causing a decrease in binding of the positively chargeddrug and release of the therapeutic agent. A target buffer can beprovided with the binding agent to reversibly couple the binding agentto the therapeutic agent. The rate of release can be controlled, forexample slowed down, by using insolubility of the buffer in thevitreous. Alternatively or in combination, the elution can be limited byusing a porous membrane or a physical property such as a size of anopening.

The ion exchange may comprise positive or negative ion exchange.

The binding agent may comprise hydrophobic interaction. For example, thebinding agent may comprise at least one binding to hydrophobic pockets,for example at least one of methyl, ethyl, propyl, butyl, t-butyl orphenyl functional groups.

The binding agent may comprise affinity, for example at least one of amacromolecular affinity or a metal chelation affinity. Examples caninclude a hydroxyapatite, or chelated metal, for example zinc.Iminodiacetic acid can be chelated with zinc.

The binding agent may comprise at least one of the following functions:charging, recharging or elution. The charging may comprise a porousmaterial injected therein so as to release the active ingredient. Theporous matter may have an extremely large inert surface area, whichsurface area is available for binding. The recharging may compriseremoving carrier+therapeutic agent; and adding freshly “charged”carrier+therapeutic agent.

The elution may comprise a byproduct, for example unbound binding agentthat can be removed. For example, a mechanism such as diffusion or plugflow of of vitreous may change a condition such as pH so as to reduceinteraction of therapeutic agent and carriers.

Additionally or in the alternative, a sustained drug delivery system ofthe therapeutic agent may comprise drug delivery packets; e.g.,microspheres that are activated. The packets can be activated with atleast one of photochemical activation, thermal activation orbiodegradation.

The therapeutic device may comprise at least one structure configured toprovide safety precautions. The device may comprise at least onestructure to prevent at least one of macrophage or other immune cellwithin the reservoir body; bacterial penetration; or retinal detachment.

The therapeutic device may be configured for other applications in thebody. Other routes of administration of drugs may include at least oneof intraocular, oral, subcutaneous, intramuscular, intraperitoneal,intranasal, dermal, intrathecal, intravascular, intra articular,pericardial, intraluminal in organs and gut or the like.

Conditions that may be treated and/or prevented using the drug deliverydevice and method described herein may include at least one of thefollowing: hemophilia and other blood disorders, growth disorders,diabetes, leukemia, hepatitis, renal failure, HIV infection, hereditarydiseases such as cerebrosidase deficiency and adenosine deaminasedeficiency, hypertension, septic shock, autoimmune diseases such asmultiple sclerosis, Graves disease, systemic lupus erythematosus andrheumatoid arthritis, shock and wasting disorders, cystic fibrosis,lactose intolerance, Crohn's disease, inflammatory bowel disease,gastrointestinal or other cancers, degenerative diseases, trauma,multiple systemic conditions such as anemia, and ocular diseases suchas, for example, retinal detachment, proliferative retinopathy,proliferative diabetic retinopathy, degenerative disease, vasculardiseases, occlusions, infection caused by penetrating traumatic injury,endophthalmitis such as endogenous/systemic infection, post-operativeinfections, inflammations such as posterior uveitis, retinitis orchoroiditis and tumors, such as neoplasms and retinoblastoma.

Examples of therapeutic agents 110 that may be delivered by thetherapeutic device 100 are described in Table 1A and may includeTriamcinolone acetonide, Bimatoprost (Lumigan), Ranibizumab (Lucentis™),Travoprost (Travatan, Alcon), Timolol (Timoptic, Merck), Levobunalol(Betagan, Allergan), Brimonidine (Alphagan, Allergan), Dorzolamide(Trusopt, Merck), Brinzolamide (Azopt, Alcon). Additional examples oftherapeutic agents that may be delivered by the therapeutic deviceinclude antibiotics such as tetracycline, chlortetracycline, bacitracin,neomycin, polymyxin, gramicidin, cephalexin, oxytetracycline,chloramphenicol kanamycin, rifampicin, ciprofloxacin, tobramycin,gentamycin, erythromycin and penicillin; antifungals such asamphotericin B and miconazole; anti-bacterials such as sulfonamides,sulfadiazine, sulfacetamide, sulfamethizole and sulfisoxazole,nitrofurazone and sodium propionate; antivirals such as idoxuridine,trifluorotymidine, acyclovir, ganciclovir and interferon;antiallergenics such as sodium cromoglycate, antazoline, methapyriline,chlorpheniramine, pyrilamine, cetirizine and prophenpyridamine;anti-inflammatories such as hydrocortisone, hydrocortisone acetate,dexamethasone, dexamethasone 21-phosphate, fluocinolone, medrysone,prednisolone, prednisolone 21-phosphate, prednisolone acetate,fluoromethalone, betamethasone, and triamcinolone; non-steroidalanti-inflammatories such as salicylate, indomethacin, ibuprofen,diclofenac, flurbiprofen and piroxicam; decongestants such asphenylephrine, naphazoline and tetrahydrozoline; miotics andanticholinesterases such as pilocarpine, salicylate, acetylcholinechloride, physostigmine, eserine, carbachol, diisopropylfluorophosphate, phospholine iodide and demecarium bromide; mydriaticssuch as atropine sulfate, cyclopentolate, homatropine, scopolamine,tropicamide, eucatropine and hydroxyamphetamine; sypathomimetics such asepinephrine; antineoplastics such as carmustine, cisplatin andfluorouracil; immunological drugs such as vaccines and immunestimulants; hormonal agents such as estrogens, estradiol,progestational, progesterone, insulin, calcitonin, parathyroid hormoneand peptide and vasopressin hypothalamus releasing factor; betaadrenergic blockers such as timolol maleate, levobunolol Hcl andbetaxolol Hcl; growth factors such as epidermal growth factor,fibroblast growth factor, platelet derived growth factor, transforminggrowth factor beta, somatotropin and fibronectin; carbonic anhydraseinhibitors such as dichlorophenamide, acetazolamide and methazolamideand other drugs such as prostaglandins, antiprostaglandins andprostaglandin precursors. Other therapeutic agents known to thoseskilled in the art which are capable of controlled, sustained releaseinto the eye in the manner described herein are also suitable for use inaccordance with variations described herein.

The therapeutic agent 110 may comprise one or more of the following:Abarelix, Abatacept, Abciximab, Adalimumab, Aldesleukin, Alefacept,Alemtuzumab, Alpha-1-proteinase inhibitor, Alteplase, Anakinra,Anistreplase, Antihemophilic Factor, Antithymocyte globulin, Aprotinin,Arcitumomab, Asparaginase, Basiliximab, Becaplermin, Bevacizumab,Bivalirudin, Botulinum Toxin Type A, Botulinum Toxin Type B, Capromab,Cetrorelix, Cetuximab, Choriogonadotropin alfa, Coagulation Factor IX,Coagulation factor VIIa, Collagenase, Corticotropin, Cosyntropin,Cyclosporine, Daclizumab, Darbepoetin alfa, Defibrotide, Denileukindiftitox, Desmopressin, Dornase Alfa,Drotrecogin alfa, Eculizumab,Efalizumab, Enfuvirtide, Epoetin alfa, Eptifibatide, Etanercept,Exenatide, Felypressin, Filgrastim, Follitropin beta, Galsulfase,Gemtuzumab ozogamicin, Glatiramer Acetate, Glucagon recombinant,Goserelin, Human Serum Albumin, Hyaluronidase, Ibritumomab, Idursulfase,Immune globulin, Infliximab, Insulin Glargine recombinant, InsulinLyspro recombinant, Insulin recombinant, Insulin, porcine, InterferonAlfa-2a, Recombinant, Interferon Alfa-2b, Recombinant, Interferonalfacon-1, Interferonalfa-n1, Interferon alfa-n3, Interferon beta-1b,Interferon gamma-1b, Lepirudin, Leuprolide, Lutropin alfa, Mecasermin,Menotropins, Muromonab, Natalizumab, Nesiritide, Octreotide, Omalizumab,Oprelvekin, OspA lipoprotein, Oxytocin, Palifermin, Palivizumab,Panitumumab, Pegademase bovine, Pegaptanib, Pegaspargase, Pegfilgrastim,Peginterferon alfa-2a, Peginterferon alfa-2b, Pegvisomant, Pramlintide,Ranibizumab, Rasburicase, Reteplase, Rituximab, Salmon Calcitonin,Sargramostim, Secretin, Sermorelin, Serum albumin iodonated, Somatropinrecombinant, Streptokinase, Tenecteplase, Teriparatide, ThyrotropinAlfa, Tositumomab, Trastuzumab, Urofollitropin, Urokinase, orVasopressin. The molecular weights of the molecules and indications ofthese therapeutic agents are set for below in Table 1A, below.

The therapeutic agent 110 may comprise one or more of compounds that actby binding members of the immunophilin family of cellular proteins. Suchcompounds are known as “immunophilin binding compounds.” Immunophilinbinding compounds include but are not limited to the “limus” family ofcompounds. Examples of limus compounds that may be used include but arenot limited to cyclophilins and FK506-binding proteins (FKBPs),including sirolimus (rapamycin) and its water soluble analog SDZ-RAD,tacrolimus, everolimus, pimecrolimus, CCI-779 (Wyeth), AP23841 (Ariad),and ABT-578 (Abbott Laboratories).

The limus family of compounds may be used in the compositions, devicesand methods for the treatment, prevention, inhibition, delaying theonset of, or causing the regression of angiogenesis-mediated diseasesand conditions of the eye, including choroidal neovascularization. Thelimus family of compounds may be used to prevent, treat, inhibit, delaythe onset of, or cause regression of AMD, including wet AMD. Rapamycinmay be used to prevent, treat, inhibit, delay the onset of, or causeregression of angiogenesis-mediated diseases and conditions of the eye,including choroidal neovascularization. Rapamycin may be used toprevent, treat, inhibit, delay the onset of, or cause regression of AMD,including wet AMD.

The therapeutic agent 110 may comprise one or more of: pyrrolidine,dithiocarbamate (NF.kappa.B inhibitor); squalamine; TPN 470 analogue andfumagillin; PKC (protein kinase C) inhibitors; Tie-1 and Tie-2 kinaseinhibitors; inhibitors of VEGF receptor kinase; proteosome inhibitorssuch as Velcade™ (bortezomib, for injection; ranibuzumab (Lucentis™) andother antibodies directed to the same target; pegaptanib (Macugen™);vitronectin receptor antagonists, such as cyclic peptide antagonists ofvitronectin receptor-type integrins; .alpha.-v/.beta.-3 integrinantagonists; .alpha.-v/.beta.-1 integrin antagonists; thiazolidinedionessuch as rosiglitazone or troglitazone; interferon, including.gamma.-interferon or interferon targeted to CNV by use of dextran andmetal coordination; pigment epithelium derived factor (PEDF);endostatin; angiostatin; tumistatin; canstatin; anecortave acetate;acetonide; triamcinolone; tetrathiomolybdate; RNA silencing or RNAinterference (RNAi) of angiogenic factors, including ribozymes thattarget VEGF expression; Accutane™ (13-cis retinoic acid); ACEinhibitors, including but not limited to quinopril, captopril, andperindozril; inhibitors of mTOR (mammalian target of rapamycin);3-aminothalidomide; pentoxifylline; 2-methoxyestradiol; colchicines;AMG-1470; cyclooxygenase inhibitors such as nepafenac, rofecoxib,diclofenac, rofecoxib, NS398, celecoxib, vioxx, and(E)-2-alkyl-2(4-methanesulfonylphenyl)-1-phenylethene; t-RNA synthasemodulator; metalloprotease 13 inhibitor; acetylcholinesterase inhibitor;potassium channel blockers; endorepellin; purine analog of6-thioguanine; cyclic peroxide ANO-2; (recombinant) arginine deiminase;epigallocatechin-3-gallate; cerivastatin; analogues of suramin; VEGFtrap molecules; apoptosis inhibiting agents; Visudyne™, snET2 and otherphoto sensitizers, which may be used with photodynamic therapy (PDT);inhibitors of hepatocyte growth factor (antibodies to the growth factoror its receptors, small molecular inhibitors of the c-met tyrosinekinase, truncated versions of HGF e.g. NK4).

The therapeutic agent 110 may comprise a combination with othertherapeutic agents and therapies, including but not limited to agentsand therapies useful for the treatment of angiogenesis orneovascularization, particularly CNV. Non-limiting examples of suchadditional agents and therapies include pyrrolidine, dithiocarbamate(NF.kappa.B inhibitor); squalamine; TPN 470 analogue and fumagillin; PKC(protein kinase C) inhibitors; Tie-1 and Tie-2 kinase inhibitors;inhibitors of VEGF receptor kinase; proteosome inhibitors such asVelcade™; bortezomib, for injection; ranibuzumab (Lucentis™) and otherantibodies directed to the same target; pegaptanib (Macugen™);vitronectin receptor antagonists, such as cyclic peptide antagonists ofvitronectin receptor-type integrins; alpha-v/beta-3 integrinantagonists; alpha-v/beta-1 integrin antagonists; thiazolidinedionessuch as rosiglitazone or troglitazone; interferon, including.gamma.-interferon or interferon targeted to CNV by use of dextran andmetal coordination; pigment epithelium derived factor (PEDF);endostatin; angiostatin; tumistatin; canstatin; anecortave acetate;acetonide; triamcinolone; tetrathiomolybdate; RNA silencing or RNAinterference (RNAi) of angiogenic factors, including ribozymes thattarget VEGF expression; Accutane™ (13-cis retinoic acid); ACEinhibitors, including but not limited to quinopril, captopril, andperindozril; inhibitors of mTOR (mammalian target of rapamycin);3-aminothalidomide; pentoxifylline; 2-methoxyestradiol; colchicines;AMG-1470; cyclooxygenase inhibitors such as nepafenac, rofecoxib,diclofenac, rofecoxib, NS398, celecoxib, vioxx, and(E)-2-alkyl-2(4-methanesulfonylphenyl)-1-phenylethene; t-RNA synthasemodulator; metalloprotease 13 inhibitor; acetylcholinesterase inhibitor;potassium channel blockers; endorepellin; purine analog of6-thioguanine; cyclic peroxide ANO-2; (recombinant) arginine deiminase;epigallocatechin-3-gallate; cerivastatin; analogues of suramin; VEGFtrap molecules; inhibitors of hepatocyte growth factor (antibodies tothe growth factor or its receptors, small molecular inhibitors of thec-met tyrosine kinase, truncated versions of HGF e.g. NK4); apoptosisinhibiting agents; Visudyne™, snET2 and other photo sensitizers withphotodynamic therapy (PDT); and laser photocoagulation.

The therapeutic agents may be used in conjunction with apharmaceutically acceptable carrier such as, for example, solids such asstarch, gelatin, sugars, natural gums such as acacia, sodium alginateand carboxymethyl cellulose; polymers such as silicone rubber; liquidssuch as sterile water, saline, dextrose, dextrose in water or saline;condensation products of castor oil and ethylene oxide, liquid glyceryltriester of a lower molecular weight fatty acid; lower alkanols; oilssuch as corn oil, peanut oil, sesame oil, castor oil, and the like, withemulsifiers such as mono- or di-glyceride of a fatty acid, or aphosphatide such as lecithin, polysorbate 80, and the like; glycols andpolyalkylene glycols; aqueous media in the presence of a suspendingagent, for example, sodium carboxymethylcellulose, sodium hyaluronate,sodium alginate, poly(vinyl pyrrolidone) and similar compounds, eitheralone, or with suitable dispensing agents such as lecithin,polyoxyethylene stearate and the like. The carrier may also containadjuvants such as preserving, stabilizing, wetting, emulsifying agentsor other related materials.

The therapeutic device may comprise a container configured to hold atleast one therapeutic agent, the container comprising a chamber to holdthe at least one therapeutic agent with at least one opening to releasethe at least one therapeutic agent to the vitreous humor and porousstructure 150 placed within the at least one opening. The porousstructure 150 may comprise a fixed tortuous, porous material such as asintered metal, a sintered glass or a sintered polymer with a definedporosity and tortuosity that controls the rate of delivery of the atleast one therapeutic agent to the vitreous humor. The rigid porousstructures provide certain advantages over capillary tubes, erodiblepolymers and membranes as a mechanism for controlling the release of atherapeutic agent or agents from the therapeutic device. Theseadvantages include the ability of the rigid porous structure to comprisea needle stop, simpler and more cost effective manufacture, flushabilityfor cleaning or declogging either prior to or after implantation, highefficiency depth filtration of microorganisms provided by the labyrinthsof irregular paths within the structure and greater robustness due togreater hardness and thickness of the structure compared to a membraneor erodible polymer matrix. Additionally, when the rigid porousstructure is manufactured from a sintered metal, ceramic, glass orcertain plastics, it can be subjected to sterilization and cleaningprocedures, such as heat or radiation based sterilization anddepyrogenation that might damage polymer and other membranes. In certainvariations, as illustrated in example 9, the rigid porous structure maybe configured to provide a therapeutically effective, concentration ofthe therapeutic agent in the vitreous for at least 6 months. Thisrelease profile provided by certain configurations of the rigid porousstructures enables a smaller device, which is preferred in a small organsuch as the eye where larger devices may alter or impair vision.

FIG. 6A-1 shows a therapeutic device 100 comprising a container 130having a penetrable barrier 184 disposed on a first end, a porousstructure 150 disposed on a second end to release therapeutic agent foran extended period, and a retention structure 120 comprising anextension protruding outward from the container to couple to the scleraand the conjunctiva. The extending protrusion of the retention structuremay comprise a diameter 120D. The retention structure may comprise anindentation 120I sized to receive the sclera. The container may comprisea tubular barrier 160 that defines at least a portion of the reservoir,and the container may comprise a width, for example a diameter 134. Thediameter 134 can be sized within a range, for example within a rangefrom about 0.5 to about 4 mm, for example within a range from about 1 to3 mm and can be about 2 mm, for example. The container may comprise alength 136, sized so as to extend from the conjunctiva to the vitreousto release the therapeutic agent into the vitreous. The length 136 canbe sized within a range, for example within a range from about 2 toabout 14 mm, for example within a range from about 4 to 10 mm and can beabout 7 mm, for example. The volume of the reservoir may besubstantially determined by an inner cross-sectional area of the tubularstructure and distance from the porous structure to the penetrablebarrier. The retention structure may comprise an annular extensionhaving a retention structure diameter greater than a diameter of thecontainer. The retention structure may comprise an indentationconfigured to receive the sclera when the extension extends between thesclera and the conjunctive. The penetrable barrier may comprise a septumdisposed on a proximal end of the container, in which the septumcomprises a barrier that can be penetrated with a sharp object such as aneedle for injection of the therapeutic agent. The porous structure maycomprise a cross sectional area 150A sized to release the therapeuticagent for the extended period.

The porous structure 150 may comprise a first side coupled to thereservoir 150S1 and a second side to couple to the vitreous 150S2. Thefirst side may comprise a first area 150A1 and the second side maycomprise a second area 150A2. The porous structure may comprise athickness 105T. The porous structure many comprise a diameter 150D.

The volume of the reservoir 140 may comprise from about 5 uL to about2000 uL of therapeutic agent, or for example from about 10 uL to about200 uL of therapeutic agent.

The therapeutic agent stored in the reservoir of the container comprisesat least one of a solid comprising the therapeutic agent, a solutioncomprising the therapeutic agent, a suspension comprising thetherapeutic agent, particles comprising the therapeutic agent adsorbedthereon, or particles reversibly bound to the therapeutic agent. Forexample, reservoir may comprise a suspension of a cortico-steroid suchas triamcinolone acetonide to treat inflammation of the retina. Thereservoir may comprise a buffer and a suspension of a therapeutic agentcomprising solubility within a range from about 1 ug/mL to about 100ug/mL, such as from about 1 ug/mL to about 40 ug/mL. For example, thetherapeutic agent may comprise a suspension of triamcinolone acetonidehaving a solubility of approximately 19 ug/mL in the buffer at 37 C whenimplanted.

The release rate index may comprise many values, and the release rateindex with the suspension may be somewhat higher than for a solution inmany variations, for example. The release rate index may be no more thanabout 5, and can be no more than about 2.0, for example no more thanabout 1.5, and in many variations may be no more than about 1.2, so asto release the therapeutic agent with therapeutic amounts for theextended time.

The therapeutic device, including for example, the retention structureand the porous structure, may be sized to pass through a lumen of acatheter.

The porous structure may comprise a needle stop that limits penetrationof the needle. The porous structure may comprise a plurality of channelsconfigured for the extended release of the therapeutic agent. The porousstructure may comprise a rigid sintered material having characteristicssuitable for the sustained release of the material.

FIG. 6A-2 shows a therapeutic device as in FIG. 6A-1 comprising arounded distal end.

FIG. 6B shows a rigid porous structure as in FIG. 6A-1. The rigid porousstructure 158 comprises a plurality of interconnecting channels 156. Theporous structure comprises a sintered material composed ofinterconnected grains 155 of material. The interconnected grains ofmaterial define channels that extend through the porous material torelease the therapeutic agent. The channels may extend around thesintered grains of material, such that the channels compriseinterconnecting channels extending through the porous material.

The rigid porous structure can be configured for injection of thetherapeutic agent into the container in many ways. The channels of therigid porous structure may comprise substantially fixed channels whenthe therapeutic agent is injected into the reservoir with pressure. Therigid porous structure comprises a hardness parameter within a rangefrom about 160 Vickers to about 500 Vickers. In some variations therigid porous structure is formed from sintered stainless steel andcomprises a hardness parameter within a range from about 200 Vickers toabout 240 Vickers. In some variations it is preferred to inhibitejection of the therapeutic agent through the porous structure duringfilling or refilling the reservoir of the therapeutic device with afluid. In these variations the channels of the rigid porous structurecomprise a resistance to flow of an injected solution or suspensionthrough a thirty gauge needle such that ejection of said solution orsuspension through the rigid porous structure is substantially inhibitedwhen said solution or suspension is injected into the reservoir of thetherapeutic device. Additionally, these variations may optionallycomprise an evacuation vent or an evacuation reservoir under vacuum orboth to facilitate filling or refilling of the reservoir.

The reservoir and the porous structure can be configured to releasetherapeutic amounts of the therapeutic agent in many ways. The reservoirand the porous structure can be configured to release therapeuticamounts of the therapeutic agent corresponding to a concentration of atleast about 0.1 ug per ml of vitreous humor for an extended period of atleast about three months. The reservoir and the porous structure can beconfigured to release therapeutic amounts of the therapeutic agentcorresponding to a concentration of at least about 0.1 ug per ml ofvitreous humor and no more than about 10 ug per ml for an extendedperiod of at least about three months. The therapeutic agent maycomprise at least a fragment of an antibody and a molecular weight of atleast about 10 k Daltons. For example, the therapeutic agent maycomprise one or more of ranibizumab or bevacizumab. Alternatively or incombination, the therapeutic agent may comprise a small molecule drugsuitable for sustained release. The reservoir and the porous structuremay be configured to release therapeutic amounts of the therapeuticagent corresponding to a concentration of at least about 0.1 ug per mlof vitreous humor and no more than about 10 ug per ml for an extendedperiod of at least about three months or at least about six months. Thereservoir and the porous structure can be configured to releasetherapeutic amounts of the therapeutic agent corresponding to aconcentration of at least about 0.1 ug per ml of vitreous humor and nomore than about 10 ug per ml for an extended period of at least abouttwelve months or at least about two years or at least about three years.The reservoir and the porous structure may also be configured to releasetherapeutic amounts of the therapeutic agent corresponding to aconcentration of at least about 0.01 ug per ml of vitreous humor and nomore than about 300 ug per ml for an extended period of at least about 3months or 6 months or 12 months or 24 months.

The channels of the rigid porous structure comprise a hydrogelconfigured to limit a size of molecules passed through the channels ofthe rigid porous structure. For example, the hydrogel can be formedwithin the channels and may comprise an acrylamide gel. The hydrogelcomprises a water content of at least about 70%. For example, thehydrogel may comprise a water content of no more than about 90% to limitmolecular weight of the therapeutic agent to about 30 k Daltons. Thehydrogel comprises a water content of no more than about 95% to limitmolecular weight of the therapeutic agent to about 100 k Daltons. Thehydrogel may comprise a water content within a range from about 90% toabout 95% such that the channels of the porous material are configuredto pass Lucentis™ and substantially not pass Avastin™.

The rigid porous structure may comprise a composite porous material thatcan readily be formed in or into a wide range of different shapes andconfigurations. For example, the porous material can be a composite of ametal, aerogel or ceramic foam (i.e., a reticulated intercellularstructure in which the interior cells are interconnected to provide amultiplicity of pores passing through the volume of the structure, thewalls of the cells themselves being substantially continuous andnon-porous, and the volume of the cells relative to that of the materialforming the cell walls being such that the overall density of theintercellular structure is less than about 30 percent theoreticaldensity) through pores of which are impregnated with a sintered powderor aerogel. The thickness, density, porosity and porous characteristicsof the final composite porous material can be varied to conform with thedesired release of the therapeutic agent.

Variations comprise a method of making an integral (i.e.,single-component) porous structure. The method may comprise introducingparticles into a mold having a desired shape for the porous structure.The shape includes a proximal end defining a plurality of proximalporous channel openings to couple to the reservoir, a distal enddefining a plurality of outlet channel openings to couple to thevitreous humor of the eye, a plurality of blind inlet cavities extendinginto the filter from the proximal openings, and a plurality of blindoutlet cavities extending into the porous structure from the outletchannel openings. The method further includes applying pressure to themold, thereby causing the particles to cohere and form a singlecomponent, and sintering the component to form the porous structure. Theparticles can be pressed and cohere to form the component without theuse of a polymeric binder, and the porous structure can be formedsubstantially without machining.

The mold can be oriented vertically with the open other end disposedupwardly, and metal powder having a particle size of less than 20micrometers can be introduced into the cavity through the open end ofthe mold while vibrating the mold to achieve substantially uniformpacking of the metal powder in the cavity. A cap can be placed on theopen other end of the mold, and pressure is applied to the mold andthereby to the metal powder in the cavity to cause the metal powder tocohere and form a cup-shaped powdered metal structure having a shapecorresponding to the mold. The shaped powdered metal structure can beremoved from the mold, and sintered to obtain a porous sintered metalporous structure.

The metal porous structure can be incorporated into the device by apress fit into an impermeable structure with an opening configured toprovide a tight fit with the porous structure. Other means, such aswelding, can be used to incorporate the porous structure into thedevice. Alternatively, or in combination, the powdered metal structurecan be formed in a mold where a portion of the mold remains with theshaped powdered metal structure and becomes part of the device. This maybe advantageous in achieving a good seal between the porous structureand the device.

The release rate of therapeutic agent through a porous body, such as asintered porous metal structure or a porous glass structure, may bedescribed by diffusion of the therapeutic agent within the porousstructure with the channel parameter, and with an effective diffusioncoefficient equal to the diffusion coefficient of the therapeutic agentin the liquid that fills the reservoir multiplied by the Porosity and aChannel Parameter of the porous body:

Release Rate=(D P/F)A(c _(R) −c _(V))/L,

where:c_(R)=Concentration in reservoirc_(V)=Concentration outside of the reservoir or in the vitreousD=Diffusion coefficient of the therapeutic agent in the reservoirsolutionP=Porosity of porous structureF=Channel parameter that may correspond to a tortuosity parameter ofchannels of porous structureA=Area of porous structureL=Thickness (length) of porous structure

Cumulative Release=1−cR/cR0=1−exp((−D PA/FL V _(R))t),

wheret=time, Vr=reservoir volume

The release rate index can (hereinafter “RRI”) be used to determinerelease of the therapeutic agent. The RRI may be defined as (PA/FL), andthe RRI values herein will have units of mm unless otherwise indicated.Many of the porous structures used in the therapeutic delivery devicesdescribed herein have an RRI of no more than about 5.0, often no morethan about 2.0, and can be no more than about 1.2 mm.

The channel parameter can correspond to an elongation of the path of thetherapeutic agent released through the porous structure. The porousstructure may comprise many interconnecting channels, and the channelparameter can correspond to an effective length that the therapeuticagent travels along the interconnecting channels of the porous structurefrom the reservoir side to the vitreous side when released. The channelparameter multiplied by the thickness (length) of the porous structurecan determine the effective length that the therapeutic agent travelsalong the interconnecting channels from the reservoir side to thevitreous side. For example, the channel parameter (F) of about 1.5corresponds to interconnecting channels that provide an effectiveincrease in length traveled by the therapeutic agent of about 50%, andfor a 1 mm thick porous structure the effective length that thetherapeutic agent travels along the interconnecting channels from thereservoir side to the vitreous side corresponds to about 1.5 mm. Thechannel parameter (F) of at least about 2 corresponds to interconnectingchannels that provide an effective increase in length traveled by thetherapeutic agent of about 100%, and for a 1 mm thick porous structurethe effective length that the therapeutic agent travels along theinterconnecting channels from the reservoir side to the vitreous sidecorresponds to at least about 2.0 mm. As the porous structure comprisesmany interconnecting channels that provide many alternative paths forrelease of the therapeutic agent, blockage of some of the channelsprovides no substantial change in the effective path length through theporous structure as the alternative interconnecting channels areavailable, such that the rate of diffusion through the porous structureand the release of the therapeutic agent are substantially maintainedwhen some of the channels are blocked.

If the reservoir solution is aqueous or has a viscosity similar towater, the value for the diffusion coefficient of the therapeutic agent(TA) in water at the temperature of interest may be used. The followingequation can be used to estimate the diffusion coefficient at 37° C.from the measured value of D_(BSA,20C)=6.1 e-7 cm2/s for bovine serumalbumin in water at 20° C. (Molokhia et al, Exp Eye Res 2008):

D _(TA,37C) =D _(BSA,20C)(η_(20C)/η_(37C))(MW _(BSA) MW _(TA))^(1/3)

whereMW refers to the molecular weight of either BSA or the test compound andη is the viscosity of water. The following lists diffusion coefficientsof proteins of interest.

Diff Coeff Compound MW Temp C. (cm{circumflex over ( )}2/s) BSA 69,00020 6.1E−07 BSA 69,000 37 9.1E−07 Ranibizumab 48,000 20 6.9E−07Ranibizumab 48,000 37 1.0E−06 Bevacizumab 149,000 20 4.7E−07 Bevacizumab149,000 37 7.1E−07Small molecules have a diffusion coefficient similar to fluorescein(MW=330, D=4.8 to 6 e-6 cm²/s from Stay, M S et al. Pharm Res 2003,20(1), pp. 96-102). For example, the small molecule may comprise aglucocorticoid such as triamcinolone acetonide having a molecular weightof about 435.

The porous structure comprises a porosity, a thickness, a channelparameter and a surface area configured to release therapeutic amountsfor the extended period. The porous material may comprise a porositycorresponding to the fraction of void space of the channels extendingwithin the material. The porosity comprises a value within a range fromabout 3% to about 70%. In other variations, the porosity comprises avalue with a range from about 5% to about 10% or from about 10% to about25%, or for example from about 15% to about 20%. Porosity can bedetermined from the weight and macroscopic volume or can be measured vianitrogen gas adsorption

The porous structure may comprise a plurality of porous structures, andthe area used in the above equation may comprise the combined area ofthe plurality of porous structures.

The channel parameter may comprise a fit parameter corresponding to thetortuosity of the channels. For a known porosity, surface area andthickness of the surface parameter, the curve fit parameter F, which maycorrespond to tortuosity of the channels can be determined based onexperimental measurements. The parameter PA/FL can be used to determinethe desired sustained release profile, and the values of P, A, F and Ldetermined. The rate of release of the therapeutic agent corresponds toa ratio of the porosity to the channel parameter, and the ratio of theporosity to the channel parameter can be less than about 0.5 such thatthe porous structure releases the therapeutic agent for the extendedperiod. For example, the ratio of the porosity to the channel parameteris less than about 0.1 or, for example, less than about 0.2 such thatthe porous structure releases the therapeutic agent for the extendedperiod. The channel parameter may comprise a value of at least about 1,such as at least about 1.2. For example, the value of the channelparameter may comprise at least about 1.5, for example at least about 2,and may comprise at least about 5. The channel parameter can be within arange from about 1.1 to about 10, for example within a range from about1.2 to about 5. The channel parameter to release the therapeutic agentfor an intended release rate profile can be determined empirically.

The area in the model originates from the description of masstransported in units of flux; i.e., rate of mass transfer per unit area.For simple geometries, such as a porous disc mounted in an impermeablesleeve of equal thickness, the area corresponds to one face of the discand the thickness, L, is the thickness of the disc. For more complexgeometries, such as a porous body in the shape of a truncated cone, theeffective area is a value in between the area where therapeutic agententers the porous body and the area where therapeutic agent exits theporous body.

A model can be derived to describe the release rate as a function oftime by relating the change of concentration in the reservoir to therelease rate described above. This model assumes a solution oftherapeutic agent where the concentration in the reservoir is uniform.In addition, the concentration in the receiving fluid or vitreous isconsidered negligible (c_(V)=0). Solving the differential equation andrearrangement yields the following equations describing theconcentration in the reservoir as a function of time, t, and volume ofthe reservoir, V_(R), for release of a therapeutic agent from a solutionin a reservoir through a porous structure.

c _(R) =c _(R0)exp((−D PA/FL V _(R))t)

and Cumulative Release=1−c_(R)/c_(R0)

When the reservoir contains a suspension, the concentration inreservoir, c_(R), is the dissolved concentration in equilibrium with thesolid (i.e., the solubility of the therapeutic agent). In this case, theconcentration in the reservoir is constant with time, the release rateis zero order, and the cumulative release increases linearly with timeuntil the time when the solid is exhausted.

Therapeutic concentrations for many ophthalmic therapeutic agents may bedetermined experimentally by measuring concentrations in the vitreoushumor that elicit a therapeutic effect. Therefore, there is value inextending predictions of release rates to predictions of concentrationsin the vitreous. A one-compartment model may be used to describeelimination of therapeutic agent from eye tissue.

Current intravitreal administration of therapeutic agents such asLucentis™ involves a bolus injection. A bolus injection into thevitreous may be modeled as a single exponential with rate constant,k=0.693/half-life and a cmax=dose/V_(v) where V_(v) is the vitreousvolume. As an example, the half-life for ranibizumab is approximately 3days in the rabbit and the monkey (Gaudreault et al.) and 9 days inhumans (Lucentis' package insert). The vitreous volume is approximately1.5 mL for the rabbit and monkey and 4.5 mL for the human eye. The modelpredicts an initial concentration of 333 ug/mL for a bolus injection of0.5 mg Lucentis™ into the eye of a monkey. This concentration decays toa vitreous concentration of 0.1 ug/mL after about a month.

For devices with extended release, the concentration in the vitreouschanges slowly with time. In this situation, a model can be derived froma mass balance equating the release rate from the device (described byequations above) with the elimination rate from the eye, k c_(v) V_(v).Rearrangement yields the following equation for the concentration in thevitreous:

c_(v)=Release rate from device/k V_(v).

Since the release rate from a device with a solution of therapeuticagent decreases exponentially with time, the concentration in thevitreous decreases exponentially with the same rate constant. In otherwords, vitreous concentration decreases with a rate constant equal to DPA/FL V_(R) and, hence, is dependent on the properties of the porousstructure and the volume of the reservoir.

Since the release rate is zero order from a device with a suspension oftherapeutic agent, the vitreous concentration will also betime-independent. The release rate will depend on the properties of theporous structure via the ratio, PA/FL, but will be independent of thevolume of the reservoir until the time at which the drug is exhausted.

The channels of the rigid porous structure can be sized in many ways torelease the intended therapeutic agent. For example, the channels of therigid porous structure can be sized to pass therapeutic agent comprisingmolecules having a molecular weight of at least about 100 Daltons or forexample, at least about 50 k Daltons. The channels of the rigid porousstructure can be sized to pass therapeutic agent comprising moleculescomprising a cross-sectional size of no more than about 10 nm. Thechannels of the rigid porous structure comprise interconnecting channelsconfigured to pass the therapeutic agent among the interconnectingchannels. The rigid porous structure comprises grains of rigid materialand wherein the interconnecting channels extend at least partiallyaround the grains of rigid material to pass the therapeutic agentthrough the porous material. The grains of rigid material can be coupledtogether at loci of attachment and wherein the interconnecting channelsextend at least partially around the loci of attachment.

The porous structure and reservoir may be configured to release theglucocorticoid for an extended time of at least about six months with atherapeutic amount of glucocorticoid of corresponding to an in situconcentration within a range from about 0.05 ug/mL to about 4 ug/mL, forexample from 0.1 ug/mL to about 4 ug/mL, so as to suppress inflammationin the retina-choroid.

The porous structure comprises a sintered material. The sinteredmaterial may comprise grains of material in which the grains comprise anaverage size of no more than about 20 um. For example, the sinteredmaterial may comprise grains of material in which the grains comprise anaverage size of no more than about 10 um, an average size of no morethan about 5 um, or an average size of no more than about 1 um. Thechannels are sized to pass therapeutic quantities of the therapeuticagent through the sintered material for the extended time based on thegrain size of the sintered material and processing parameters such ascompaction force and time and temperature in the furnace. The channelscan be sized to inhibit penetration of microbes including bacteria andfungal spores through the sintered material.

The sintered material comprises a wettable material to inhibit bubbleswithin the channels of the material.

The sintered material comprises at least one of a metal, a ceramic, aglass or a plastic. The sintered material may comprise a sinteredcomposite material, and the composite material comprises two or more ofthe metal, the ceramic, the glass or the plastic. The metal comprises atleast one of Ni, Ti, nitinol, stainless steel including alloys such as304, 304L, 316 or 316L, cobalt chrome, elgiloy, hastealloy, c-276 alloyor Nickel 200 alloy. The sintered material may comprise a ceramic. Thesintered material may comprise a glass. The plastic may comprise awettable coating to inhibit bubble formation in the channels, and theplastic may comprise at least one of polyether ether ketone (PEEK),polyethylene, polypropylene, polyimide, polystyrene, polycarbonate,polyacrylate, polymethacrylate, or polyamide.

The rigid porous structure may comprise a plurality of rigid porousstructures coupled to the reservoir and configured to release thetherapeutic agent for the extended period. For example, additional rigidporous structure can be disposed along the container, for example theend of the container may comprise the porous structure, and anadditional porous structure can be disposed along a distal portion ofthe container, for example along a tubular sidewall of the container.

The therapeutic device can be tuned to release therapeutic amounts ofthe therapeutic agent above the minimum inhibitory concentration for anextended time based on bolus injections of the therapeutic agent. Forexample, the volume of the chamber of the reservoir can be sized withthe release rate of the porous structure based on the volume of thebolus injection. A formulation of a therapeutic agent can be provided,for example a known intravitreal injection formulation. The therapeuticagent can be capable of treating the eye with bolus injections, suchthat the formulation has a corresponding period between each of thebolus injections to treat the eye. For example the bolus injections maycomprise monthly injections. Each of the bolus injections comprises avolume of the formulation, for example 50 uL. Each of the bolusinjections of the therapeutic agent may correspond to a range oftherapeutic concentrations of the therapeutic agent within the vitreoushumor over the time course between injections, and the device can betuned so as to release therapeutic amounts of the therapeutic agent suchthat the vitreous concentrations of the released therapeutic agent fromthe device are within the range of therapeutic concentrations of thecorresponding bolus injections. For example, the therapeutic agent maycomprise a minimum inhibitory concentration to treat the eye, forexample at least about 3 ug/mL, and the values of the range oftherapeutic concentrations can be at least about 3 ug/mL. Thetherapeutic device can be configured to treat the eye with an injectionof the monthly volume of the formulation into the device, for examplethrough the penetrable barrier. The reservoir of the container has achamber to contain a volume of the therapeutic agent, for example 35 uL,and a mechanism to release the therapeutic agent from the chamber to thevitreous humor.

The volume of the container and the release mechanism can be tuned totreat the eye with the therapeutic agent with vitreous concentrationswithin the therapeutic range for an extended time with each injection ofthe quantity corresponding to the bolus injection, such that theconcentration of the therapeutic agent within the vitreous humor remainswithin the range of therapeutic concentrations and comprises at leastthe minimum inhibitory concentration. The extended time may comprise atleast about twice the corresponding period of the bolus injections. Therelease mechanism comprises one or more of a porous frit, a sinteredporous frit, a permeable membrane, a semi-permeable membrane, acapillary tube or a tortuous channel, nano-structures, nano-channels orsintered nano-particles. For example, the porous frit may comprise aporosity, cross-sectional area, and a thickness to release thetherapeutic agent for the extended time. The volume of the containerreservoir can be sized in many ways in relation to the volume of theinjected formulation and can be larger than the volume of injectedformulation, smaller than the volume of injected formulation, orsubstantially the same as the volume of injected formulation. Forexample, the volume of the container may comprise no more than thevolume of the formulation, such that at least a portion of theformulation injected into the reservoir passes through the reservoir andcomprises a bolus injection to treat the patient immediately. As thevolume of the reservoir is increased, the amount of formulation releasedto the eye through the porous structure upon injection can decreasealong with the concentration of active ingredient of the therapeuticagent within the reservoir, and the release rate index can be increasedappropriately so as to provide therapeutic amounts of therapeutic agentfor the extended time. For example, the volume of the reservoir of thecontainer can be greater than the volume corresponding to the bolusinjection, so as to provide therapeutic amounts for at least about fivemonths, for example six months, with an injection volume correspondingto a monthly injection of Lucentis™. For example, the formulation maycomprise Lucentis™ modified in accordance with variations, 50 uL, andthe reservoir may comprise a volume of about 100 uL and providetherapeutic vitreous concentrations of at least about 3 ug/mL for sixmonths with 50 uL of Lucentis™ injected into the reservoir.

The chamber may comprise a substantially fixed volume and the releaserate mechanism comprises a substantially rigid structure to maintainrelease of the therapeutic agent above the minimum inhibitoryconcentration for the extended time with each injection of a pluralityof injections.

A first portion of the injection may pass through the release mechanismand treat the patient when the formulation is injected, and a secondportion of the formulation can be contained in the chamber when theformulation is injected.

FIG. 6B-1 shows interconnecting channels 156 extending from first side150S1 to second side 150S2 of the porous structure as in FIG. 6B. Theinterconnecting channels 156 extend to a first opening 158A1, a secondopening 158A2 and an Nth opening 158AN on the first side 150S1. Theinterconnecting channels 156 extend to a first opening 158B1, a secondopening 158B2 and an Nth opening 158BN on the second side 150S2. Each ofthe openings of the plurality of channels on the first side is connectedto each of the openings of plurality of channels on the second side,such that effective length traveled along the channels is greater thanthickness 150T. The channel parameter can be within a range from about1.1 to about 10, such that the effective length is within a range fromabout 1.1 to 10 times the thickness 150T. For example, the channelparameter can be about 1 and the porosity about 0.2, such that theeffective length corresponds to at least about 5 times the thickness150T.

The rigid porous structure can be shaped and molded in many ways forexample with tubular shapes, conical shapes, discs and hemisphericalshapes. The rigid porous structure may comprise a molded rigid porousstructure. The molded rigid porous structure may comprise at least oneof a disk, a helix or a tube coupled to the reservoir and configured torelease the therapeutic agent for the extended period.

The formulation can be injected into many therapeutic devices, forexample as described in U.S. Pat. Nos. 5,466,233; 5,972,369; 6,719,750;and U.S. Patent Publication No. 2003/0014036 A1.

The porous structure 150 may comprise a plurality of elongatenano-channels extending from a first side of the porous structure to asecond side of the porous structure. The porous structure 150 maycomprise a rigid material having the holes formed thereon, and the holesmay comprise a maximum dimension across such as a diameter. The diameterof the nano-channels may comprise a dimension across, for example fromabout 10 nm across, to about 1000 nm across, or larger. The channels maybe formed with etching of the material, for example lithographic etchingof the material. The channels may comprise substantially straightchannels such that the channel parameter F comprises about 1, and theparameters area A, and thickness or length L correspond to the combinedcross-sectional area of the channels and the thickness or length of theporous structure.

The porous structure 150 may comprise interconnecting nano-channels, forexample formed with a sintered nano-material.

The injection of therapeutic agent into the device 100 as describedherein can be performed before implantation into the eye oralternatively when the therapeutic device is implanted into the eye.

FIG. 7 shows a therapeutic device 100 coupled to an injector 701 thatremoves material from the device and injects therapeutic agent 702 intothe device. The injector picks up spent media 703 and refills thetherapeutic device with fresh therapeutic agent. The therapeutic agentis injected into the therapeutic device. The spent media is pulled upinto the injector. The injector may comprise a stopper mechanism 704.

The injector 701 may comprise a first container 702C to contain aformulation of therapeutic agent 702 and a second container 703C toreceive the spent media 703. Work in relation to variations suggeststhat the removal of spent media 703 comprising material from thecontainer reservoir of the therapeutic device can remove particulatefrom the therapeutic device, for example particles comprised ofaggregated therapeutic agent such as protein. The needle 189 maycomprise a double lumen needle with a first lumen coupled to the firstcontainer and a second lumen coupled to the second container, such thatspent media 703 passes from the container reservoir of device 100 to theinjector. A valve 703V, for example a vent, can be disposed between thesecond lumen and the second container. When the valve is open andtherapeutic agent is injected, spent media 703 from the containerreservoir of the therapeutic device 100 passes to the second containerof the injector, such that at least a portion of the spent media withinthe therapeutic device is exchanged with the formulation. When the valveis closed and the therapeutic agent is injected, a portion of thetherapeutic agent passes from the reservoir of the therapeutic deviceinto the eye. For example, a first portion of formulation of therapeuticagent can be injected into therapeutic device 100 when the valve is opensuch that the first portion of the formulation is exchanged withmaterial disposed within the reservoir; the valve is then closed and asecond portion of the formulation is injected into therapeutic device100 such that at least a portion of the first portion passes through theporous structure into the eye. Alternatively or in combination, aportion of the second portion of injected formulation may pass throughthe porous structure when the second portion is injected into the eye.The second portion of formulation injected when the valve is closed maycorrespond to a volume of formulation that passes through the porousstructure into the vitreous humor to treat the patient immediately.

The needle 189 may comprise a dual lumen needle, for example asdescribed in U.S. patent application Ser. No. 12/696,678, filed Jan. 29,2010, entitled “POSTERIOR SEGMENT DRUG DELIVERY,” published Oct. 7, 2010as U.S. Patent Publication No. 2010/0255061, the full disclosure ofwhich has been previously incorporated herein by reference.

The penetrable barrier 184, for example the septum, can be inserted intothe access port 180. The penetrable barrier may comprise an elasticmaterial sized such that the penetrable barrier can be inserted into theaccess port 180. The penetrable barrier may comprise one or more elasticmaterials such as siloxane or rubber. The penetrable barrier maycomprise tabs 184T to retain the penetrable barrier in the access port.The penetrable barrier 184 may comprise a beveled upper rim 184R sizedto seal the access port 180. The access port 180 of the reservoircontainer 130 may comprise a beveled upper surface to engage the beveledrim and seal the penetrable barrier against the access port 180 when thetabs 184T engage an inner annular or elongate channel of the accessport. The penetrable barrier 184 may comprise an opaque material, forexample a grey material, for example silicone, such that the penetrablebarrier can be visualized by the patient and treating physician.

The reservoir container 130 of the device may comprise a rigidbiocompatible material that extends at least from the retentionstructure to the rigid porous structure, such that the reservoircomprises a substantially constant volume when the therapeutic agent isreleased with the rigid porous structure so as to maintain a stablerelease rate profile, for example when the patient moves. Alternativelyor in combination, the reservoir container 130 may comprise an opticallytransmissive material such that the reservoir container 130 can betranslucent, for example transparent, such that the chamber of reservoir140 can be visualized when the device is loaded with therapeutic agentoutside the patient prior to implantation, for example when injectedwith a formulation of therapeutic agent prior to implantation in thephysician's office. This visualization of the reservoir 140 can behelpful to ensure that the reservoir 140 is properly filled withtherapeutic agent by the treating physician or assistant prior toimplantation. The reservoir container may comprise one or more of manybiocompatible materials such as acrylates, polymethylmethacrylate,siloxanes, metals, titanium stainless steel, polycarbonate,polyetheretherketone (PEEK), polyethylene, polyethylene terephthalate(PET), polyimide, polyamide-imide, polypropylene, polysulfone,polyurethane, polyvinylidene fluoride or PTFE. The biocompatiblematerial of the reservoir container may comprise an opticallytransmissive material such as one or more of acrylate, polyacrylate,methlymethacraylate, polymethlymethacrylate (PMMA), polyacarbonate orsiloxane. The reservoir container 130 can be machined from a piece ofmaterial, or injection molded, so as to form the retention structure 120comprising flange 122 and the elongate narrow portion 120NE. The flange122 may comprise a translucent material such that the physician canvisualize tissue under the flange to assess the patient and to decreaseappearance of the device 100 when implanted. The reservoir container 130may comprise a channel extending along axis 100A from the access port180 to porous structure 150, such that formulation injected into device100 can be released in accordance with the volume of the reservoir andrelease rate of the porous structure 150, as described herein. Theporous structure 150 can be affixed to the distal end of therapeuticdevice 100, for example with glue. Alternatively or in combination, thedistal end of the reservoir container 130 may comprise an inner diametersized to receive the porous structure 150, and the reservoir container130 may comprise a stop to position the porous structure 150 at apredetermined location on the distal end so as to define a predeterminedsize of reservoir 140.

TUNING OF THERAPEUTIC DEVICE FOR SUSTAINED RELEASE BASED ON AN INJECTIONOF A FORMULATION OF THERAPEUTIC AGENT HAVING ONE OR MORE OF A LARGEMOLECULAR WEIGHT STABILIZER, ERODIBLE PARTICLES, OR BINDING AGENTPARTICLES, OR COMBINATIONS THEREOF

The tuned release can be used to determine the release of thetherapeutic agent and stabilizer combined with one or more of thebinding agent or erodible material as described herein. One or more ofcalculations, computer modeling, numerical simulations or finite elementanalysis can be used to determine the release rate profile of thetherapeutic agent, as described herein. The affect of one or more of thestabilizer, reversible binding agent particles, or erodible particles onthe modulation of the rate of release can be determined, for example.

In many variations, the stabilizer may comprise a molecular weight thatcorresponds to at least about 20% of the molecular weight of thetherapeutic agent.

The amount of stabilizer and release rate profile of the stabilizerthrough the porous structure can be determined based on theconcentration of the stabilizer, the volume of the reservoir, and therelease rate index of the porous structure 150. The release rate profilemay also include the fraction of stabilizer complexed with thetherapeutic agent and the corresponding diffusion coefficient of thecomplexed therapeutic agent.

The reversible binding characteristics of the therapeutic agent andbinding agent can be used to determine the release rate profile. Theamount of therapeutic agent in solution, the amount of therapeutic agentcomplexed with the stabilizer, and the amount of therapeutic agentreversibly bound to the binding agent can be determined, for example asa function of pH. The amount of therapeutic agent in solution and theamount of therapeutic agent complexed with the stabilizer andcorresponding diffusion coefficients can be used to determine the rateof release of the therapeutic agent through the porous structure. Therate of release of therapeutic agent through the porous structure maycomprise the rate of release of the therapeutic agent in solution andthe therapeutic agent complexed with the stabilizer.

In many variations, the binding agent is sized such that diffusionthrough the porous structure is substantially inhibited, and theparticles of binding agent may have dimensions greater than the channelsof the porous structure 150, or smaller than the channels of the porousstructure. For example, particles greater than 5 um may not pass throughthe porous structure, even when there is convection of fluid through theporous structure such as when the device is refilled with formulation(i.e., the particles may be trapped in the porous structure as in adepth filter or may be trapped on the surface of the porous structure asin a surface filter). Although particles having a size as large as thesize of the channels of porous structure 150 may pass through thechannels of the porous structure under convection, these particles mayhave no substantial diffusive flux because the diffusion coefficient maybe substantially larger than the diffusion coefficient of thetherapeutic agent. For example, particles having a size of about 0.050um (50 nm) may have a diffusion coefficient that is about one tenth ofthe diffusion coefficient of ranibizumab, for example. The particles maycomprise a size within a range from about 50 um to about 0.5 um, forexample, based substantially on the molecular weight of the therapeuticagent and the size of the channels of the porous structure 150.

The rate of erosion of the erodible particles can be used to determinethe rate of generation of protons to maintain the pH in the reservoirchamber below about 7. The rate of generation of protons may correspondto one or more of the pH, ionic strength or osmolarity of the componentsof the formulation 190 in the reservoir chamber of the device.

The therapeutic device 100 can be tuned to deliver a target therapeuticconcentration profile based on the volume of formulation injected intothe device. The injected volume may comprise a substantially fixedvolume, for example within about +/−30% of an intended predeterminedtarget volume. The volume of the reservoir can be sized with the releaserate index so as to release the therapeutic agent for an extended timesubstantially greater than the treatment time of a corresponding bolusinjection. The device can also be tuned to release the therapeutic agentbased on the half-life of the therapeutic agent in the eye. The devicevolume and release rate index comprise parameters that can be tunedtogether based on the volume of formulation injected and the half-lifeof the therapeutic agent in the eye. The following equations can be usedto determine therapeutic device parameters suitable for tuning thedevice.

Rate=Vr(dCr/dt)=−D(PA/TL)Cr

where Rate=Rate of release of therapeutic agent from deviceCr=concentration of therapeutic agent in reservoirVr=volume of reservoirD=Diffusion constant

PA/TL=RRI

P=porosityA=areaT=tortuosity=F=channel parameter.For a substantially fixed volume injection,

Cr0=(Injection Volume)(Concentration of Formulation)/Vr

Where Cr0=initial concentration in reservoir following injection offormulation

For Injection Volume=50 uL

Cr0=(0.05 mL)(10 mg/mL)/Vr(1000 ug/1 mg)=500 ug/Vr

Rate=x(500 ug)exp(−xt)

where t=time

x=(D/Vr)(PA/TL)

With a mass balance on the vitreousVv(dCv/dt)=Rate from device=kVvCvwhere Vv=volume of vitreous (about 4.5 ml)Cv=concentration of therapeutic agent in vitreousk=rate of drug from vitreous (proportional to 1/half-life of drug invitreous)For the situation appropriate for the variations as described hereinwhere Cv remains substantially constant and changes slowly with time(i.e. dCv/dt is approximately 0),Cv=(Rate from device)/(kVv)Since kVv is substantially constant, the max value of Cv will correspondto conditions that maximize the Rate from the device. At a given timesince injection into the device (e.g., 180 days), the maximum Cv isfound at the value of x that provides the maximum rate. The optimalvalue of x satisfiesd(Rate)/dx=0 at a given time.

Rate=500(x)exp(−xt)=f(x)g(x) where f(x)=500x and g(x)=exp(−xt)

d(Rate)/dx=f(x)g(x)+f(x)g′(x)=500(1−xt)exp(−xt)

For a given time, t, d(Rate)/dx=0 when 1−xt=0 and xt=1The rate is maximum when (D/Vr)(PA/TL)t=1.For a given volume, optimal PA/TL=optimal RRI=Vr/(Dt)Therefore the highest Cv at a given time, t, occurs for the optimalRRI=(PA/FL) for a given Vr.Also, the ratio (Vr)/(RRI)=(Vr)/(PA/TL)=Dt will determine the optimalrate at the time.

The above equations provide approximate optimized values that, whencombined with numerical simulations, can provide optimal values of Vrand PA/TL. The final optimum value can depend on additional parameters,such as the filling efficiency.

The above parameters can be used to determine the optimal RRI, and thetherapeutic device can be tuned to the volume of formulation injectedinto the device with a device reservoir volume and release rate indexwithin about +/−50% of the optimal values, for example +/−30% of theoptimal values. For example, for an optimal release rate index of theporous structure and an optimal reservoir volume sized to receive apredetermined quantity of therapeutic agent, e.g., 50 uL, so as toachieve therapeutic concentrations above a minimum inhibitoryconcentration for a predetermined extended time such as 90 days, themaximum volume of the reservoir can be limited to no more than abouttwice the optimal volume. This tuning of the reservoir volume and theporous structure to the injected volume of the formulation can increasethe time of release of therapeutic amounts from the device as comparedto a much larger reservoir volume that receives the same volume ofinjectable formulation. Although many examples as described herein showa porous frit structure and reservoir volume tuned together to receive aquantity of formulation and provide release for an extended time, theporous structure tuned with the reservoir may comprise one or more of aporous frit, a permeable membrane, a semi-permeable membrane, acapillary tube or a tortuous channel, nano-structures, nano-channels orsintered nano-particles, and the release rate characteristics can bedetermined, for example a release rate index, so as to tune the one ormore porous structures and the volume to receive the quantity of theformulation and release therapeutic amounts for an extended time.

As an example, the optimal RRI at 180 days can be determined for areservoir volume of about 125 uL. Based on the above equations(Vr/Dt)=optimal RRI, such that the optimal RRI at 180 days is about0.085 for the 50 uL formulation volume injected into the device. Thecorresponding Cv is about 3.19 ug/mL at 180 days based on the Rate ofdrug released from the device at 180 days and the rate of the drug fromthe vitreous (k corresponding to a half life of about 9 days). A devicewith a container reservoir volume of 63 uL and RRI of 0.044 will alsoprovide the optimal Cv at 180 days since the ratio of Vr to PA/TL isalso optimal. Although an optimal value can be determined, thetherapeutic device can be tuned to provide therapeutic amounts of drugat a targeted time, for example 180 days, with many values of thereservoir volume and many values of the release rate index near theoptimal values, for example within about +/−50% of the optimal values.Although the volume of the reservoir can be substantially fixed, thevolume of the reservoir can vary, for example within about +/−50% aswith an expandable reservoir such as a balloon reservoir.

The half-life of the drug in the vitreous humor of the eye can bedetermined based on the therapeutic agent and the type of eye, forexample human, rabbit or monkey, such that the half-life may bedetermined based on the species of the eye, for example. With at leastsome animal models the half life of the therapeutic agent in thevitreous humor can be shorter than for human eyes, for example by afactor of about two in at least some instances. For example, thehalf-life of the therapeutic agent Lucentis™ (ranibizumab) can be aboutnine days in the human eye and about two to four days in the rabbit andmonkey animal models. For small molecules, the half life in the vitreoushumor of the human eye can be about two to three hours and can be aboutone hour in the monkey and rabbit animal models. The therapeutic devicecan be tuned to receive the volume of formulation based on the half-lifeof the therapeutic agent in the human vitreous humor, or an animalvitreous humor, or combinations thereof. The half life of thetherapeutic agent in the eye can be determined empirically based on thetype of eye and the therapeutic agent, such that the reservoir andporous structure can be tuned together so as to receive the volume offormulation and provide therapeutic amounts for the extended time.

The formulation 190 may comprise components that result in slowing thediffusion of the therapeutic agent until those components are depletedvia release to the vitreous (i.e., effective diffusion coefficient forthe therapeutic agent that is lower than that in a dilute solution ofthe therapeutic agent in water). This may occur due to an increase inthe viscosity of the formulation or due to interactions. The componentthat slows down diffusion may be a high concentration of the therapeuticagent itself. As time proceeds, depletion of the component maycorrespond to an increase in diffusion coefficient of the therapeuticagent, thereby generating a release profile that is more constant.

Soluble, high molecular weight species that interact with thetherapeutic agent 110 of interest can be added to the formation. Theinteraction of the therapeutic agent 110 and the high molecular weightspecies will modulate the diffusion of the therapeutic agent 110 throughthe solution, and thus affect the release rate of the therapeutic agent110 from the device 100.

Insoluble resins such as ion exchange resins or resins containinghydrophobic groups that reversibly bind the therapeutic agent 110 ofinterest can be added to the formulation. The interaction of the resinsand the therapeutic agent 110 will affect the concentration of thetherapeutic agent 110 in solution, and thus modulate the release rate ofthe therapeutic agent 110 from the device 100.

High molecular weight stabilizers can be added to the formulation of thetherapeutic agent 110 of interest. If the molecular weight of thestabilizer is approximately the same as that of the therapeutic agent110, the two will diffuse from the therapeutic device 100 atapproximately the same rate, thus keeping the ratio of stabilizer totherapeutic agent 110 approximately constant over time. If the molecularweight of the stabilizer is higher than that of the therapeutic agent110, the ratio of stabilizer to therapeutic agent 110 in the device willactually increase over time. Both of these scenarios may increase thestability of the therapeutic agent 110 in the device during the deliveryperiod.

FIG. 8A shows an apparatus comprising a first container 110C having theformulation 190 of therapeutic agent and the second container comprisinga syringe 188 having erodible material 196 to generate a proton of anacid. The particles of erodible material can be mixed with theformulation of therapeutic agent within about one day or less prior toinjection such that erosion of the material is decreased and also tomaintain the pH of the formulation above about 4.5, for example. Thefirst container 110C may contain formulation 190 comprising thetherapeutic agent 110, the stabilizer 192 and the reversible bindingagent 194, and may contain a buffer such as a phosphate buffer, forexample. The second container may comprise particles of erodiblematerial in a substantially dry configuration so as to decrease erosionof the erodible material.

FIG. 8B shows the syringe 188 as in FIG. 8A used to prepare theformulation of therapeutic agent prior to injection. A needle 189 can beinserted into container 110C and the formulation 190 drawn into thesecond container comprising syringe 188 so as to mix the formulationprior to injection into therapeutic device 100. The mixed formulationcan be exchanged and the syringe may comprise an exchange syringe, forexample.

FIG. 8C shows an apparatus comprising a first container having acommercially available formulation 110F of therapeutic agent, and thesecond container comprising a syringe 188 having one or more of, astabilizer 192, a binding agent 194 comprising porous particles, or anerodible material 196 to generate a proton of an acid, in accordancewith variations;

FIG. 8D shows the first and second containers as in FIG. 8C used toprepare the formulation 190 of therapeutic agent prior to injection. Aneedle 189 can be inserted into container 110C and the formulation 110Fdrawn into the second container comprising syringe 188 so as to mix andprovide the formulation 190 prior to injection into therapeutic device100. The mixed formulation can be exchanged and the syringe may comprisean exchange syringe, for example. The mixed formulation 190 prior toinjection may comprise the therapeutic agent 110, and one or more of astabilizer 192, a binding agent 194 comprising porous particles, or anerodible material 196 to generate a proton of an acid. For example,prior to drawing formulation 110F, the syringe 188 may comprise astabilizer 192 and an erodible material 196 as a substantially drycombination, and the formulation 110F of container 110C may compriseLucentis™. Upon drawing an amount of the commercially availableformulation of Lucentis™ into the syringe, the formulation 190 can beprovided for injection into therapeutic device 100. Syringe 188 maycomprise a substantially single use disposable syringe, for example.

The first and second containers can be configured in many ways. Forexample, the second container may comprise a cartridge having theerodible material stored therein, in which the cartridge is configuredto couple to a syringe having the formulation of the therapeutic agentcontained therein, so as to mix the erodible material with theformulation upon injection into or exchange with a therapeutic device.The cartridge may be configured to couple to the needle and the syringe.For example, the cartridge may comprise a first end to couple to thesyringe and a second end to couple to a needle. The container maycomprise an amount of the particles corresponding to a volume of thereservoir chamber of the device so as to combine with an amount of theformulation corresponding to the volume of the reservoir chamber, so asto provide a concentration of particles and formulation loaded intodevice 100 corresponding to an intended target concentration ofparticles and formulation.

Determination of Isoelectric Point of Ranibizumab

Determining the isoelectric point of a protein can be used to determinethe stability of a protein formulation, or to develop a related assay.The isoelectric point of Lucentis™ can be estimated from the primaryamino acid sequence obtained from the Novartis package insert ofLucentis™ marketed in Australia, CAS number 347396-82-1.

The total number of ionizable acidic and basic amino acids weretabulated. The pKa values of the ionizable side groups were estimatedusing the Sigma-Aldrich table available on the World Wide Web(sigmaaldrich.com/life-science/metabolomics/bioultra-reagents/amino-acids.html).

The local environments in a protein can shift pKa values of single aminoacids, but average values should be useful to estimate the overalleffect. Table Y1 is a list of the sequence number position and totalnumber of the acidic and basic amino acids present in Lucentis™. Theacidic groups of Asp and Glu total 32 amino acids (pKa ˜4), and thebasic groups of Tyr, Lys, and Arg, (pKa˜10) total 61 amino acids.Therefore with twice as many basic groups as acidic groups, Lucentis™would be classified as a basic protein with an isoelectric point ofabout 8.0 to 9.0. After estimating the number of charges versus pH of asolution including the N-terminus and C-terminus, the plot in FIG. 4Cshows the zero net charge state (isoelectric point) to be achieved atabout pH 8.0 to 9.0.

TABLE Y1 LucentisTM Amino Acid Positions and Total Number Asp Glu HisTyr Lys Arg A-chain 28 1 31 27 43 19 63 6 107 32 65 38 73 46 174 54 7666 90 57 210 60 98 67 111 89 230 80 127 87 154 158 94 139 218 222 95 153227 99 211 101 216 102 219 103 220 109 224 155 228 186 204 B-chain 1 8155 32 39 18 17 105 189 36 42 61 28 123 198 49 45 108 70 143 86 103 14282 161 87 107 211 122 165 91 126 151 187 140 145 167 195 173 149 170 213186 169 175 192 183 188 190 207 Total A & B 18 16 8 25 26 10

The charge as a function of pH can be determined for many therapeuticagents as described herein, for example protein based therapeutic agentscomprising a Fab antibody fragment and derivatives thereof.

EXPERIMENTAL

Experiments to determine empirically the release rate of the therapeuticagent and the stabilizer from the formulation 190 are described herein.

Example 1

A drug release study was performed using bovine serum albumin (BSA) as amodel therapeutic agent and fluorescein as a model stabilizer, so as toshow formation of ionic complexes between a model stabilizer and modeltherapeutic agent, in which the model stabilizer comprises on or more ofan ionic group, a hydroxyl group, or an aromatic ring and thetherapeutic agent comprises Fab antibody fragment. Similar complexes canbe formed with higher molecular weight stabilizers as described herein,so as to decrease the rate of release of the therapeutic agent.

The release rate of BSA and fluorescein were measured from devicesinitially loaded with formulations listed in Table E1. Buffer containingtrehalose, polysorbate 20, and histidine was prepared first and pH wasadjusted to 5.5 using HCl. Then BSA and fluorescein was added and pH wasdetermined by pH paper to be in the 6.1-6.5 and 6.6-7.0 range forFormulations I and II respectively.

Devices were fabricated containing sintered porous titanium cylinders(Mott Corporation) with a diameter of 0.038 inches and a thickness of0.030 inches. The porous cylinders were mounted into devices machinedfrom poly (methyl methacrylate) with a reservoir volume of 0.025 mL anda silicone septum. The devices expose one planar face of the poroustitanium to the solution in the reservoir and the other planar face tothe receiver solution in the vials.

The devices (n=6 or 7 for each formulation) were filled with 0.05 mLformulation using a tuberculin syringe and a 33 gauge needle insertedthrough the septum. Excess formulation was expressed through the poroustitanium and rinsed off the device prior to the start of the drugrelease study by submerging in phosphate buffered saline (PBS). Thedevices were mounted on hangers to suspend the devices in the center ofPBS in 1.5 mL microcentrifuge tubes. At periodic intervals, thereservoirs were moved to new tubes containing degassed PBS as thereceiver fluid. The amount of BSA transported from the reservoir throughthe porous cylinder into the receiver fluid was determined by measuringthe amount of BSA in the vials using a Micro BCA™ Protein Assay kit(Pierce, 23235) on a Molecular Devices Plate Reader. Fluoresceinconcentrations in the receiver fluid were determined from absorbance at492 nm on the plate reader.

TABLE E1 Compositions of formulations injected into devices FormulationI II BSA (mg/mL) 20 200 Fluorescein (mg/mL) 1 1 Trehalose (wt %) 10 10Polysorbate 20 (wt %) 0.01 0.01 Histidine HCl (M) 0.01 0.01 Sodium azide(wt %) 0.02 0.02

FIG. 9 shows calibration curves for absorbance of fluorescein in PBSversus PBS containing 100 and 1000 ug/mL BSA as the calibration curvediluent. For a given concentration of fluorescein, the fluoresceinabsorbance was lower in the standards containing BSA. When the standardscontaining BSA were assayed using the standards without BSA, thefluorescein concentrations were 74 and 69% of nominal values BSAconcentrations of 100 and 1000 ug/mL, respectively, over a fluoresceinconcentration range of 2 to 30 ug/mL. It is known that fluoresceinabsorbance is stronger for the dianion form than the other ionic formsof fluorescein (Smith et al., Water S A, 28(4), 2002, 395-402). Thelower absorbance from addition of BSA is consistent with formation of anionic complex between fluorescein and BSA that may lower theconcentration of fluorescein dianion in solution. Hence, the release offluorescein in the presence of BSA is an example of a model stabilizerthat forms an ionic complex with the model therapeutic agent.

Table E2 shows the concentrations of BSA and fluorescein measured in thereceiver fluid at the start of the release study. The initial releaserate of BSA is proportional to the BSA concentration, suggesting theeffective diffusion coefficient was not dependent on concentration ofBSA. Concentrations of fluorescein are corrected for the impact of thepresence of BSA concentration measured in each sample, as describedabove. The release rate of fluorescein from the formulation containing200 mg/mL BSA is slower by a factor of two compared to the formulationcontaining 20 mg/mL. The slower release rate can be described by aneffective diffusion coefficient that is lower by a factor of two. Theseresults demonstrate the ability to slow down diffusion and drug releaseof a model stabilizer by formation of ionic complexes between a modelstabilizer and model therapeutic agent.

TABLE E2 Measured concentrations and initial release rates of BSA andfluorescein from Formulations I and II. Formulation I Formulation II (20mg/mL (200 mg/mL BSA) BSA) Mean SD Mean SD Measured BSA in Receiver 1054 1154 135 (ug/mL) Measured fluorescein in Receiver 10.9 0.5 4.6 0.5(ug/mL) BSA rate (ug/mL) 13.3 0.5 147.8 18.4 BSA rate, normalized byinitial 0.665 0.026 0.739 0.092 BSA conc Fluorescein rate (ug/mL), 1.40.1 0.6 0.1 uncorrected Correction factor 0.74 0.74 0.69 0.69Fluorescein rate (ug/mL), corrected 1.9 0.1 0.8 0.1

Example 2 Erodible Particles

PLGA may be purchased from a number of supplies, for example, PURASORB®of Purac Biomaterials, RESOMER® of Boehringer Ingelheim, LakeshoreBiomaterials™ of Surmodics Pharmaceuticals and Lactel® of Durect. PLGAis available with a range of properties as stock or custom polymers. Forexample, Durect produces PLGA with time for resorption ranging from afew months to greater than 24 months. Any commercially available PLGAcan be processed into monodisperse microspheres by using processes knownin the art, such as single and double emulsion processing schemes. PLGAmay be purchased as microparticles. For example, monodisperse PURASORB®PLGA 5004 microspheres are available from Nanomi with particle sizesranging from 1 to 30 um, prepared by an emulsification technology, andsupplied freeze-dried.

Microparticles 1 um in size from Naomi can be added to Lucentis™ atconcentrations ranging from 0.01% to 1%. The microparticles can be addedjust prior to injection into devices. Control devices can also beinjected with Lucentis™ only. Drug release testing could be performed asdescribed in Example 1. The stability of ranibizumab could be tested byassays such as ELISA and Ion-Exchange Chromatography HPLC on samples ofdrug in the receiver fluid. In addition, the contents in the reservoirof the devices could be harvested to assay for drug stability andmeasurement of pH by, for example, pH paper.

Example 3 Stabilizers

Various forms (e.g., cellulose acetate, ethylcellulose,carboxymethylcellulose, methylcellulose) and molecular weights ofcellulose can be purchased from suppliers such as Spectrum Chemicals andSigma-Aldrich. Excipients can be removed from Lucentis™ by dialysis toobtain ranibizumab. Then, excipients of choice can be added to preparethe desired formulations. An example would be 10 mg/mL ranibizumab, 10%carboxymethyl cellulose with a molecular weight of about 10 kDa, 0.01%polysorbate 20, 10 mM histidine HCl pH 5.5.

Devices can be injected with the various formulations and Lucentis™ as acontrol and subjected to drug release testing and stability assays asdescribed in Example 2.

Example 4 Stabilizers and Erodible Particles

Stabilizers can be encapsulated into erodible particles using single anddouble emulsion techniques. PLGA and stabilizers listed in Examples 2and 4 and buffers such as histidine hydrochloride can be dissolved insolvents such as dichloromethane, tetrahydrofuran, ethyl acetate,chloroform, hexafluoroisopropanol, and acetone. Surfactant such aspolysorbate 20 at concentrations on the order of 0.01% can be added towater and the PLGA and stabilizers dissolved in solvent, and sonicationapplied to form an emulsion. Solvent can be removed to yield theparticles. The particles can be added to Lucentis™ at concentrations onthe order of 1%. Devices can be injected with the various formulationsand Lucentis™ as a control and subjected to drug release testing andstability assays as described in Example 2.

Example 5 Micelle Stabilizer

Excipients can be removed from Lucentis™ by dialysis to obtainranibizumab. A series of samples can be generated with compositionidentical to Lucentis™ but with a range of polysorbate 20concentrations, from 0.0005% to 0.1%. Surface tension measurements maybe performed with a Wilhemy plate to determine the CMC; i.e.,polysorbate 20 concentration threshold for constant surface tension.Devices can then be filled with formulations containing polysorbate 20concentrations that are 0, 1, 5 and 20 times the CMC. These devices canbe subjected to drug release testing and stability assays as describedin Example 2.

TABLE 1A Therapeutic Agent List Brands Molecular Generic Name(Companies) Category Indication Weight 2-Methoxyestradiol (PalomaAngiogenesis AMD analogs Pharmaceuticals) inhibitors 3-aminothalidomide13-cis retinoic acid Accutane TM (Roche Pharmaceuticals) A0003 (AqumenA0003 AMD BioPharmaceuticals) A5b1 integrin (Jerini Ophthalmic);Inhibitors of a5b1 AMD inhibitor (Ophthotech) integrin AbarelixPlenaxis ™ (Praecis Anti-Testosterone For palliative treatment 37731Pharmaceuticals) Agents; of advanced prostate Antineoplastic cancer.Agents Abatacept Orencia ™ (Bristol- Antirheumatic For the second line37697 Myers Squibb) Agents reduction of the signs and symptoms ofmoderate-to-severe active rheumatoid arthritis, inducing inducing majorclinical response, slowing the progression of structural damage, andimproving physical function in adult patients who have AbciximabReoPro ™; Anticoagulants; For treatment of 42632 ReoPro ™ AntiplateletAgents myocardial infarction, (Centocor) adjunct to percutaneous89oronary intervention, unstable angina ABT-578 (Abbott LimusImmunophilin Laboratories) Binding Compounds Acetonide AdalimumabHumira ™ (Abbott Antirheumatic Uveitis, AMD 25645 Laboratories) Agents;Immunomodulatory Agents Aldesleukin Proleukin ™; Antineoplastic Fortreatment of adults 61118 Proleukin ™ (Chiron Agents with metastaticrenal Corp) cell carcinoma Alefacept Amevive ™ Immunomodulatory Fortreatment of 42632 Agents; moderate to severe Immunosuppressive chronicplaque Agents psoriasis Alemtuzumab Campath ™; Antineoplastic Fortreatment of B-cell 6614 Campath ™ (ILEX Agents chronic lymphocyticPharmaceuticals leukemia LP); MabCampath ™ Alpha-1-proteinase Aralast ™(Baxter); Enzyme For treatment of 28518 inhibitor Prolastin ™ (TalecrisReplacement panacinar emphysema Biotherapeutics C Agents formerly Bayer)Alteplase Activase ™ Thrombolytic For management of 54732 (GenentechInc) Agents acute myocardial infarction, acute ischemic strok and forlysis of acute pulmonary emboli AMG-1470 Anakinra Kineret ™ (AmgenAnti-Inflammatory For the treatment of 65403 Inc) Agents, Non- adultrheumatoid Steroidal; arthritis. Antirheumatic Agents; ImmunomodulatoryAgents Anecortave acetate Angiostatin Anistreplase Eminase ™ (WulfingThrombolytic For lysis of acute 54732 Pharma GmbH) Agents pulmonaryemboli, intracoronary emboli and management of myocardial infarctionAnti-angiogenesis (Eyecopharm) Anti-angiogenesis AMD peptides peptidesAnti-angiogenesis (TRACON Pharma) Anti-angiogenesis AMD antibodies,antibodies TRC093, TRC105 Anti-angiogeric Icon-1 ™ (IconicAnti-angiogeric AMD bifunctional protein Therapeutics) bifunctionalprotein, Icon-1 Anti-endothelial growth factor Antihemophilic Advate ™;Coagulants; For the treatment of 70037 Factor Alphanate ™; ThromboticAgents hemophilia A, von Bioclate ™; Willebrand diseae and Helixate ™;Helixate Factor XIII deficiency FS ™; Hemofil M ™; Humate-P ™;Hyate:C ™; Koate- HP ™; Kogenate ™; Kogenate FS ™; Monarc-M ™;Monoclate-P ™; ReFacto ™; Xyntha ™ Antithymocyte Genzyme);Immunomodulatory For prevention of renal 37173 globulin Thymoglobulin ™Agents transplant rejection (SangStat Medical Anti-hypertensive(MacuCLEAR) Anti-hypertensive AMD MC1101 MC1101 Anti-platelet deviredgrowth factor Anti-VEGF (Neurotech); Anti-VEGF AMD Avastin ™ (NeoVista)AP23841 (Ariad) Limus Immunophilin Binding Compounds ARC1905 OphthotechComplement Cascade Inhibitor (Factor C5) Aprotinin Trasylol ™Antifibrinolytic For prophylactic use to 90569 Agents reduceperioperative blood loss and the need for blood transfusion in patientsundergoing cardiopulmonary bypass in the course of coronary arterybypass graft surgery who are at an increased risk for blood loss andblood transfusio Arcitumomab CEA-Scan ™ Diagnostic Agents; For imagingcolorectal 57561 Imaging Agents tumors Asparaginase Elspar ™ (Merck &Antineoplastic For treatment of acute 132.118 Co. Inc) Agents lympocyticleukemia and non-Hodgkins lymphoma Axitinib Tyrosine Kinase 386Inhibitors Basiliximab Simulect ™ (Novartis Immunomodulatory Forprophylactic 61118 Pharmaceuticals) Agents; treatment of kidneyImmunosuppressive transplant rejection Agents Becaplermin Regranex ™;Anti-Ulcer Agents; For topical treatment of 123969 Regranex ™ (OMJTopical skin ulcers (from Pharmaceuticals) diabetes) BevacizumabAvastin ™; Avastin ™ Antiangiogenesis For treatment of 27043 (GenentechInc) Agents; metastatic colorectal Antineoplastic cancer AgentsBivalirudin Angiomax ™; Anticoagulants; For treatment of 70037Angiomax ™ Antithrombotic heparin-induced (Medicines Co or Agentsthrombocytopenia MDCO); Angiox ™ Bortezomib Proteosome InhibitorsBosutinib Tyrosine Kinase 530 Inhibitors Botulinum Toxin BOTOX ™(Allegran Anti-Wrinkle For the treatment of 23315 Type A Inc); BOTOXAgents; cervical dystonia in Cosmetic ™ Antidystonic adults to decreasethe (Allegran Inc); Agents; severity of abnormal Botox ™; Dysport ™Neuromuscular head position and neck Blocking Agents pain associatedwith cervical dystonia. Also for the treatment of severe primaryaxillary hyperhidrosis that is inadequately managed with topicalBotulinum Toxin Myobloc ™ (Solstice Antidystonic Agents For thetreatment of 12902 Type B Neurosciences); patients with cervicalNeurobloc ™ dystonia to reduce the (Solstice severity of abnormalNeurosciences) head position and neck pain associated with cervicaldystonia. C5 inhibitor (Jerini Ophthalmic); Inhibitors of C5 AMD(Ophthotech) Cal101 Calistoga PI3Kdelta Inhibitor AMD, DME CanstatinCapromab ProstaScint ™ Imaging Agents For diagnosis of 84331 (CytogenCorp) prostate cancer and detection of intra-pelvic metastases CaptoprilACE Inhibitors CCI-779 (Wyeth) Limus Immunophilin Binding CompoundsCediranib Tyrosine Kinase 450 Inhibitors Celecoxib CyclooxygenaseInhibitors Cetrorelix Cetrotide ™ Hormone For the inhibition of 78617Antagonists; premature LH surges Infertility Agents in women undergoingcontrolled ovarian stimulation Cetuximab Erbitux ™; Erbitux ™Antineoplastic For treatment of 42632 (ImClone Systems Agents metastaticcolorectal Inc) cancer. Choriogonadotropin Novarel ™; Fertility Agents;For the treatment of 78617 alfa Ovidrel ™. Gonadotropins femaleinfertility Pregnyl ™; Profasi ™ Cilary neurotrophic (Neurotech) Cilaryneurotrophic AMD factor factor Coagulation Factor Benefix ™ (GeneticsCoagulants; For treatment of 267012 IX Institute) Thrombotic Agentshemophilia (Christmas disease). Coagulation factor NovoSeven ™ (NovoCoagulants; For treatment of 54732 VIIa Nordisk) Thrombotic Agentshemorrhagic complications in hemophilia A and B Colchicines CollagenaseCordase ™; Santyl ™ Anti-Ulcer Agents; For treatment of 138885 (AdvanceTopical chronic dermal ulcers Biofactures Corp); and severe skin burnsXiaflextm ™ Complement factor (Optherion); Complement factor AMD,Geographic H recombinant (Taligen H recombinant Atrophy Therapeutics)Compstatin (Potentia Complement Factor AMD derivative peptide,Pharmaceuticals) C3 Inhibitors; POT-4 Compstatin Derivative PeptidesCorticotropin ACTH ™; Diagnostic Agents For use as a diagnostic 33927Acethropan ™; agent in the screening Acortan ™; Acthar ™; of patientspresumed Exacthin ™; H.P. to have adrenocortical Acthar Gel ™;insufficiency. Isactid ™; Purified cortrophin gel ™; Reacthin ™;Solacthyl ™; Tubex Cosyntropin Cortrosyn ™; Diagnostic Agents For use asa diagnostic 33927 Synacthen depot ™ agent in the screening of patientspresumed to have adrenocortical insufficiency. Cyclophilins LimusImmunophilin Binding Compounds Cyclosporine Gengraf ™ (Abbott AntifungalAgents; For treatment of 32953 labs); Neoral ™ Antirheumatic transplantrejection, (Novartis); Agents; rheumatoid arthritis, Restasis ™;Dermatologic severe psoriasis Restasis ™ (Allergan Agents; Enzyme Inc);Sandimmune ™ Inhibitors; (Novartis); Immunomodulatory Sangcya ™ Agents;Immunosuppressive Agents Daclizumab Zenapax ™ Immunomodulatory Forprevention of renal 61118 (Hoffmann-La Agents; transplant rejection;Roche Inc) Immunosuppressive Uveitis Agents Darbepoetin alfa Aranesp ™(Amgen Antianemic Agents For the treatment of 55066 Inc.) anemia (fromrenal transplants or certain HIV treatment) Dasatinib Tyrosine Kinase488 Inhibitors Defibrotide Dasovas ™; Antithrombotic Defibrotide is usedto 36512 Noravid ™; Agents treat or prevent a Prociclide ™ failure ofnormal blood flow (occlusive venous disease, OVD) in the liver ofpatients who have had bone marrow transplants or received certain drugssuch as oral estrogens, mercaptopurine, and many others. Denileukindiftitox Ontak ™ Antineoplastic For treatment of 61118 Agents cutaneousT-cell lymphoma Desmopressin Adiuretin ™; Antidiuretic Agents; For themanagement 46800 Concentraid ™; Hemostatics; Renal of primary nocturnalStimate ™ Agents enuresis and indicated as antidiuretic replacementtherapy in the management of central diabetes insipidus and for themanagement of the temporary polyuria and polydipsia following headtrauma or surgery in the pitu Dexamethasone Ozurdex ™ GlucocorticoidDME, inflammation, 392 (Allergan) macular edema following branch retinalvein occlusion (BRVO) or central retinal vein occlusion (CRVO)Diclofenac Cyclooxygenase Inhibitors Dithiocarbamate NFκB InhibitorDornase Alfa Dilor ™; Dilor-400 ™; Enzyme For the treatment of 7656Lufyllin ™; Lufyllin- Replacement cystic fibrosis. (double 400 ™; Agentsstrand) Neothylline ™; Pulmozyme ™ (Genentech Inc) Drotrecogin alfaXigris ™; Xigris ™ (Eli Antisepsis Agents For treatment of 267012 Lilly& Co) severe sepsis Eculizumab Soliris ™; Soliris ™ Complement AMD188333 (Alexion Cascade Inhibitor Pharmaceuticals) (Factor C5)Efalizumab Raptiva ™; Immunomodulatory For the treatment of 128771Raptiva ™ Agents; adult patients with (Genentech Inc) Immunosuppressivemoderate to severe Agents chronic plaque psoriasis, who are candidatesfor phototherapy or systemic therapy. Endostatin Enfuvirtide Fuzeon ™;Fuzeon ™ Anti-HIV Agents; For treatment of HIV 16768 (Roche HIV FusionAIDS Pharmaceuticals) Inhibitors Epoetin alfa Epogen ™ (Amgen AntianemicAgents For treatment of 55066 Inc.); Epogin ™ anemia (from renal(Chugai); Epomax ™ transplants or certain (Elanex); Eprex ™ HIVtreatment) (Janssen-Cilag. Ortho Biologics LLC); NeoRecormon ™ (Roche);Procrit ™ (Ortho Biotech); Recormon ™ (Roche) Eptifibatide Integrilin ™;Anticoagulants; For treatment of 7128 Integrilin ™ Antiplatelet Agents;myocardial infarction (Millennium Pharm) Platelet and acute coronaryAggregation syndrome. Inhibitors Erlotinib Tyrosine Kinase 393Inhibitors Etanercept Enbrel ™; Enbrel ™ Antirheumatic Uveitis, AMD25645 (Immunex Corp) Agents; Immunomodulatory Agents Everolimus NovartisLimus Immunophilin AMD Binding Compounds, mTOR Exenatide Byetta ™;Byetta ™ Indicated as adjunctive 53060 (Amylin/Eli Lilly) therapy toimprove glycemic control in patients with Type 2 diabetes mellitus whoare taking metformin, a sulfonylurea, or a combination of both, but havenot achieved adequate glycemic control. FCFD4514S Genentech/RocheComplement AMD, Geographic Cascade Inhibitor Atrophy (Factor D)Felypressin Felipresina ™ [INN- Renal Agents; For use as an 46800Spanish]; Vasoconstrictor alternative to Felipressina ™ Agentsadrenaline as a [DCIT]; 97ocalizing agent, Felypressin ™ provided thatlocal [USAN:BAN:INN]; ischaemia is not Felypressine ™ essential.[INN-French]; Felypressinum ™ [INN-Latin]; Octapressin ™ FenretinideSirion/reVision Binding Protein AMD, Geographic Therapeutics Antagonistfor Oral Atrophy Vitamin A Filgrastim Neupogen ™ Anti-InfectiveIncreases leukocyte 28518 (Amgen Inc.) Agents; production, forAntineutropenic treatment in non- Agents; myeloid Immunomodulatorycancer, neutropenia Agents and bone marrow transplant FK605-bindingLimus Immunophilin proteins, FKBPs Binding Compounds FluocinoloneRetisert ™ (Bausch Glucocorticoid Retinal inflammation, 453 Acetonide &Lomb); Iluvien ™ diabetic macular (Alimera Sciences, edema Inc.)Follitropin beta Follistim ™ Fertility Agents For treatment of 78296(Organon); Gonal female infertility F ™; Gonal-F ™ Fumagillin GalsulfaseNaglazyme ™; Enzyme For the treatment of 47047 Naglazyme ™ Replacementadults and children (BioMarin Agents with Pharmaceuticals)Mucopolysaccharidosis VI. Gefitinib Tyrosine Kinase 447 InhibitorsGemtuzumab Mylotarg ™; Antineoplastic For treatment of acute 39826ozogamicin Mylotarg ™ (Wyeth) Agents myeloid leukemia Glatiramer AcetateCopaxone ™ Adjuvants, For reduction of the 29914 Immunologic; frequencyof relapses Immunosuppressive in patients with AgentsRelapsing-Remitting Multiple Sclerosis. Glucagon GlucaGen ™ (NovoAntihypoglycemic For treatment of 54009 recombinant Nordisk); Agentssevere hypoglycemia, Glucagon ™ (Eli also used in Lilly)gastrointestinal imaging Goserelin Zoladex ™ Antineoplastic Breastcancer; 78617 Agents; Prostate carcinoma; Antineoplastic EndometriosisAgents, Hormonal Human Serum Albutein ™ (Alpha Serum substitutes Fortreatment of 39000 Albumin Therapeutic Corp) severe blood loss,hypervolemia, hypoproteinemia Hyaluronidase Vitragan ™; Anesthetic Forincrease of 69367 Vitrase ™; Vitrase ™ Adjuvants; absorption and (IstaPharma) Permeabilizing distribution of other Agents injected drugs andfor rehydration Ibritumomab Zevalin ™ (IDEC Antineoplastic For treatmentof non- 33078 Pharmaceuticals) Agents Hodgkin's lymphoma IdursulfaseElaprase ™ (Shire Enzyme For the treatment of 47047 Pharmaceuticals)Replacement Hunter syndrome in Agents adults and children ages 5 andolder. Imatinib Tyrosine Kinase AMD, DME 494 Inhibitors Immune globulinCivacir ™; Anti-Infectives; For treatment of 42632 Flebogamma ™Immunomodulatory immunodeficiencies, (Instituto Grifols Agentsthrombocytopenic SA); Gamunex ™ purpura, Kawasaki (Talecris disease,Biotherapeutics) gammablobulinemia, leukemia, bone transplant InfliximabRemicade ™ Immunomodulatory Uveitis, AMD 25645 (Centocor Inc) Agents;Immunosuppressive Agents Insulin Glargine Lantus ™ Hypoglycemic Fortreatment of 156308 recombinant Agents diabetes (type I and II) InsulinLyspro Humalog ™ (Eli Lily); Hypoglycemic For treatment of 154795recombinant Insulin Lispro (Eli Agents diabetes (type I and II) Lily)Insulin recombinant Novolin R ™ (Novo Hypoglycemic For treatment of156308 Nordisk) Agents diabetes (type I and II) Insulin, porcine IletinII ™ Hypoglycemic For the treatment of 156308 Agents diabetes (type Iand II) Interferon Interferon Alfa-2a, Roferon A ™ Antineoplastic Fortreatment of 57759 Recombinant (Hoffmann-La Agents; Antiviral chronichepatitis C, Roche Inc); Agents hairy cell leukemia, Veldona ™ (AmarilloAIDS-related Kaposi's Biosciences) sarcoma, and chronic myelogenousleukemia. Also for the treatment of oral warts arising from HIVinfection. Interferon Alfa-2b, Intron A ™ (Schering Antineoplastic Forthe treatment of 57759 Recombinant Corp) Agents; Antiviral hairy cellleukemia, Agents; malignant melanoma, Immunomodulatory and AIDS-relatedAgents Kaposi's sarcoma. Interferon alfacon-1 Advaferon ™;Antineoplastic For treatment of hairy 57759 Infergen ™ Agents; Antiviralcell leukemia, (InterMune Inc) Agents; malignant melanoma,Immunomodulatory and AIDS-related Agents Kaposi's sarcoma Interferonalfa-n1 Wellferon ™ Antiviral Agents; For treatment of 57759(GlaxoSmithKline) Immunomodulatory venereal or genital Agents wartscaused by the Human Papiloma Virus Interferon alfa-n3 Alferon ™(Interferon Antineoplastic For the intralesional 57759 Sciences Inc.);Agents; Antiviral treatment of refractory Alferon LDO ™; Agents; orrecurring external Alferon N Injection ™ Immunomodulatory condylomataAgents 100cuminate. Interferon beta-1b Betaseron ™ (Chiron AntiviralAgents; For treatment of 57759 Corp) Immunomodulatoryrelapsing/remitting Agents multiple sclerosis Interferon gamma-Actimmune ™; Antiviral Agents; For treatment of 37835 1b Actimmune ™Immunomodulatory Chronic granulomatous (InterMune Inc) Agents disease,Osteopetrosis Lapatinib Tyrosine Kinase 581 Inhibitors LepirudinRefludan ™ Anticoagulants; For the treatment of 70037 Antithromboticheparin-induced Agents; Fibrinolytic thrombocytopenia AgentsLestaurtinib Tyrosine Kinase 439 Inhibitors Leuprolide Eligard ™ (AtrixAnti-Estrogen For treatment of 37731 Labs/QLT Inc) Agents; prostatecancer, Antineoplastic endometriosis, uterine Agents fibroids andpremature puberty Lutropin alfa Luveris ™ (Serono) Fertility Agents Fortreatment of 78617 female infertility Mecasermin Increlex ™; For thelong-term 154795 Increlex ™ (Tercica); treatment of growth Iplex failurein pediatric patients with Primary IGFD or with GH gene deletion whohave developed neutralizing antibodies to GH. It is not indicated totreat Secondary IGFD resulting from GH deficiency, malnutrition, hypothMenotropins Repronex ™ Fertility Agents For treatment of 78617 femaleinfertility Methotrexate Immunomodulatory Uveitis, DME mTOR inhibitorsMuromonab Orthoclone OKT3 ™ Immunomodulatory For treatment of organ23148 (Ortho Biotech) Agents; transplant recipients, Immunosuppressiveprevention of organ Agents rejection Natalizumab Tysabri ™Immunomodulatory For treatment of 115334 Agents multiple sclerosis.Nepafenac Cyclooxygenase Inhibitors Nesiritide Natrecor ™ Cardiac drugsFor the intravenous 118921 treatment of patients with acutelydecompensated congestive heart failure who have dyspnea at rest or withminimal activity. Nilotinib Tyrosine Kinase 530 Inhibitors NS398Cyclooxygenase Inhibitors Octreotide Atrigel ™; Anabolic Agents; Fortreatment of 42687 Longastatin ™; Antineoplastic acromegaly andSandostatin ™; Agents, Hormonal; reduction of side Sandostatin LAR ™;Gastrointestinal effects from cancer Sandostatin LAR ™ Agents; Hormonechemotherapy (Novartis) Replacement Agents Omalizumab Xolair ™(Genentech Anti-Asthmatic For treatment of 29596 Inc) Agents; asthmacaused by Immunomodulatory allergies Agents Oprelvekin Neumega ™;Coagulants; Increases reduced 45223 Neumega ™ Thrombotics plateletlevels due to (Genetics Institute chemotherapy Inc) OspA lipoproteinLYMErix ™ Vaccines For prophylactic 95348 (SmithKline treatment of LymeBeecham) Disease OT-551 (Othera) Anti-oxidant AMD eyedrop OxytocinOxytocin ™ (BAM Anti-tocolytic To assist in labor, 12722 Biotech);Pitocin ™ Agents; Labor elective labor (Parke-Davis); Induction Agents;induction, uterine Syntocinon ™ Oxytocics contraction induction (Sandoz)Palifermin Kepivance ™ Antimucositis For treatment of 138885 (Amgen Inc)Agents mucositis (mouth sores) Palivizumab Synagis ™ Antiviral AgentsFor treatment of 63689 respiratory diseases casued by respiratorysyncytial virus Panitumumab Vectibix ™; Antineoplastic For the treatmentof 134279 Vectibix ™ (Amgen) Agents EGFR-expressing, metastaticcolorectal carcinoma with disease progression on or followingfluoropyrimidine-, oxaliplatin-, and irinotecan-containing chemotherapyregimens. PDGF inhibitor (Jerini Ophthalmic); Inhibitors of PDGF AMD(Ophthotech) PEDF (pigment epithelium derived factor) PegademaseAdagen ™ (Enzon Enzyme For treatment of 36512 bovine Inc.) Replacementadenosine deaminase Agents deficiency Pegaptanib Macugen ™Oligonucleotide For the treatment of 103121 neovascular (wet) age-related macular degeneration. Pegaspargase Oncaspar ™ (EnzonAntineoplastic For treatment of acute 132.118 Inc) Agents lymphoblasticleukemia Pegfilgrastim Neulasta ™ (Amgen Anti-Infective Increasesleukocyte 28518 Inc.) Agents; production, for Antineutropenic treatmentin non- Agents; myeloid cancer, Immunomodulatory neutropenia and boneAgents marrow transplant Peginterferon alfa- Pegasys ™ AntineoplasticFor treatment of hairy 57759 2a (Hoffman-La Roche Agents; Antiviral cellleukemia, Inc) Agents; malignant melanoma, Immunomodulatory andAIDS-related Agents Kaposi's sarcoma. Peginterferon alfa- PEG-IntronAntineoplastic For the treatment of 57759 2b (Schering Corp); Agents;Antiviral chronic hepatitis C in Unitron PEG ™ Agents; patients notpreviously Immunomodulatory treated with interferon Agents alpha whohave compensated liver disease and are at least 18 years of age.Pegvisomant Somavert ™ (Pfizer Anabolic Agents; For treatment of 71500Inc) Hormone acromegaly Replacement Agents Pentoxifylline PerindozrilACE Inhibitors Pimecrolimus Limus Immunophilin Binding Compounds PKC(protein kinase C) inhibitors POT-4 Potentia/Alcon Complement AMDCascade Inhibitor (Factor C3) Pramlintide Symlin ™; Symlin ™ For themealtime 16988 (Amylin treatment of Type I and Pharmaceuticals) Type IIdiabetes in combination with standard insulin therapy, in patients whohave failed to achieve adequate glucose control on insulin monotherapy.Proteosome Velcade ™ Proteosome inhibitors inhibitors PyrrolidineQuinopril ACE Inhibitors Ranibizumab Lucentis ™ For the treatment of27043 patients with neovascular (wet) age- related macular degeneration.Rapamycin (MacuSight) Limus Immunophilin AMD (siroliums) BindingCompounds Rasburicase Elitek ™; Elitek ™ Antihyperuricemic For treatmentof 168.11 (Sanofi-Synthelabo Agents hyperuricemia, Inc); Fasturtec ™reduces elevated plasma uric acid levels (from chemotherapy) ReteplaseRetavase ™ Thrombolytic For lysis of acute 54732 (Centocor); Agentspulmonary emboli, Retavase ™ (Roche) intracoronary emboli and managementof myocardial infarction Retinal stimulant Neurosolve ™ Retinalstimulants AMD (Vitreoretinal Technologies) Retinoid(s) RituximabMabThera ™; Antineoplastic For treatment of B-cell 33078 Rituxan ™Agents non-Hodgkins lymphoma (CD20 positive) RNAI (RNA interference ofangiogenic factors) Rofecoxib Vioxx ™; Ceoxx ™; Cyclooxygenase Ceeoxx ™(Merck & Inhibitors Co.) Rosiglitazone Thiazolidinediones RuboxistaurinEli Lilly Protein Kinase C DME, diabetic 469 (PKC)-b Inhibitorperipheral retinopathy Salmon Calcitonin Calcimar ™; AntihypocalcemicFor the treatment of 57304 Miacalcin ™ Agents; post-menopausal(Novartis) Antiosteporotic osteoporosis Agents; Bone DensityConservation Agents Sargramostim Immunex ™; Anti-Infective For thetreatment of 46207 Leucomax ™ Agents; cancer and bone (Novartis);Antineoplastic marrow transplant Leukine ™; Agents; Leukine ™ (BerlexImmunomodulatory Laboratories Inc) Agents SAR 1118 SARCodeImmunomodulatory Dry eye, DME, Agent conjunctivitis SDZ-RAD LimusImmunophilin Binding Compounds Secretin SecreFlo ™; Diagnostic AgentsFor diagnosis of 50207 Secremax ™, pancreatic exocrine SecreFlo ™dysfunction and (Repligen Corp) gastrinoma Selective inhibitor of thefactor 3 complement cascade Selective inhibitor of the factor 5complement cascade Semaxanib Tyrosine Kinase 238 Inhibitors SermorelinGeref ™ (Serono Anabolic Agents; For the treatment of 47402 Pharma)Hormone dwarfism, prevention of Replacement HIV-induced weight Agentsloss Serum albumin Megatope ™ (IsoTex Imaging Agents For determinationof 39000 iodinated Diagnostics) total blood and plasma volumes SF1126Semafore Pl3k/mTOR AMD, DME Inhibition Sirolimus (MacuSight) LimusImmunophilin AMD reformulation Binding (rapamycin) Compounds siRNAmolecule (Quark siRNA molecule AMD synthetic, FTP- Pharmaceuticals)synthetic 801i-14 Somatropin BioTropin ™ (Biotech Anabolic Agents; Fortreatment of 71500 recombinant General); Hormone dwarfism, acromegalyGenotropin ™ Replacement and prevention of HIV- (Pfizer); Agents inducedweight loss Humatrope ™ (Eli Lilly); Norditropin ™ (Novo Nordisk);Nutropin ™ (Genentech Inc.); NutropinAQ ™ (Genentech Inc.); Protropin ™(Genentech Inc.); Saizen ™ (Serono SA); Serostim ™; Serostim ™ (SeronoSA); Tev-Tropin ™ (GATE) Squalamine Streptokinase Streptase ™ (AventisThrombolytic For the treatment of 90569 Behringer GmbH) Agents acuteevolving transmural myocardial infarction, pulmonary embolism, deep veinthrombosis, arterial thrombosis or embolism and occlusion ofarteriovenous cannulae Sunitinib Tyrosine Kinase 398 Inhibitors TA106Taligen Complement AMD Cascade Inhibitor (Factor B) Tacrolimus LimusImmunophilin Binding Compounds Tenecteplase TNKase ™ Thrombolytic Fortreatment of 54732 (Genentech Inc) Agents myocardial infarction andlysis of intracoronary emboli Teriparatide Apthela ™; Bone Density Forthe treatment of 66361 Forsteo ™; Forteo ™; Conservation osteoporosis inmen Fortessa ™; Agents and postmenopausal Opthia ™; Optia ™; women whoare at high Optiah ™; risk for having a Zalectra ™; fracture. Also usedto Zelletra ™ increase bone mass in men with primary or hypogonadalosteoporosis who are at high risk for fracture. TetrathiomolybdateThalidomide Celgene Anti-inflammatory, Uveitis Anti-proliferativeThyrotropin Alfa Thyrogen ™ Diagnostic Agents For detection of 86831(Genzyme Inc) residueal or recurrent thyroid cancer Tie-1 and Tie-2kinase inhibitors Toceranib Tyrosine Kinase 396 Inhibitors TositumomabBexxar ™ (Corixa Antineoplastic For treatment of non- 33078 Corp) AgentsHodgkin's lymphoma (CD20 positive, follicular) TPN 470 analogueTrastuzumab Herceptin ™ Antineoplastic For treatment of 137912(Genentech) Agents HER2-positive pulmonary breast cancer TriamcinoloneTriesence ™ Glucocorticoid DME, For treatment of 435 acetonideinflammation of the retina Troglitazone Thiazolidinediones TumistatinUrofollitropin Fertinex ™ (Serono S.A.) Fertility Agents For treatmentof 78296 female infertility Urokinase Abbokinase ™; Thrombolytic For thetreatment of 90569 Abbokinase ™ Agents 107ulmonary (Abbott embolism,coronary Laboratories) artery thrombosis and IV catheter clearanceVandetanib Tyrosine Kinase 475 Inhibitors Vasopressin Pitressin ™;Antidiuretics; For the treatment of 46800 Pressyn ™ Oxytocics; enuresis,polyuria, Vasoconstrictor diabetes insipidus, Agents polydipsia andoesophageal varices with bleeding Vatalanib Tyrosine Kinase 347Inhibitors VEGF receptor kinase inhibitor VEGF Trap Aflibercept ™Genetically DME, cancer, retinal 96600 (Regneron Engineered veinocclusion, Pharmaceuticals, Antibodies choroidal Bayer HealthCareneovascularization, AG) delay wound healing, cancer treatment VisualCycle (Acucela) Visual Cycle AMD Modulator ACU- Modulator 4229Vitamin(s) Vitronectin receptor antagonists Volociximab Ophthotechalpha5beta1 AMD Integrin Inhibitor XL765 Exelixis/Sanofi- Pl3k/mTOR AMD,DME Aventis Inhibition

TABLE 1B Surfactants Surfactants include: Iconic Anionic: based onpermanent anions (sulfate, sulfonate, phosphate) or pH-dependent anions(carboxylate): Sulfates: Alkyl sulfates: ammonium lauryl sulfate, sodiumlauryl sulfate (SDS); Alkyl ether sulfates: sodium laureth sulfate, alsoknown as sodium lauryl ether sulfate (SLES), sodium myreth sulfate;Sulfonates: Docusates: dioctyl sodium sulfosucciate; Sulfonatefluorosurfactants: perfluorooctanesulfonate (PFOS),perfluorobutanesulfonate; Alkyl benzne sulfonates; Phosphates: Alkylaryl ether phosphate Alkyl ether phosphate Carboxylates: Alkylcarboxylates: Fatty acid salts (soaps): sodium stearate; Sodium lauroylsarcosinate; Carboxylate fluorsurfactants: perfluoronoanoate,perfluoroocanoate (PFOA OR PFO) Cationic: based on: pH-dependentprimary, secondary or tertiary amines become positively charged at pH<10, secondary amines become charged at pH <4: Octenidinedihydrochloride; Permanently charged quaternary ammonium cation:Alkyltrimethylammonium sals: cetyl trimthylammonium bromide (CTAB)a.k.a. hexadecyl trimethyl ammonium bromide, cetyl trimethylammoniumchloride (CTAC); Cetylpyridinium chloride (CPC); Polyethoxylated tallowamine (POEA); Benzalkonium chloride (BAC); Benzethonium chloride (BZT);5-Bromo-5-nitro-1,2-dioxane; Dimethyldioctadecylammonium chlorideDioctadecyldimethylammonium bromide (DODAB) . . . Zitterionic(amphoteric): based on primary, secondary or tertiary amines oruaternary ammonium cation with: Sulfonates: CHAPS(3-[(3-Cholamidopropyl)dimethylammonio]-1-propanesulfonate); Sultaines:cocamidopropyl hyroxysultaine; Carboxylates: Amino acids Imino acidsBetaines: cocamidopropyl betaine; Phosphates: lecithin . . . NonionicFatty alcohol, Stearyl alcohol, Cetostearyl alcohol (consistentlypredominantly of cetyl and stearyl alcohols), Oleyl alcohol;Polyoxyethylene glycol alkyl ethers (Brij):CH₃—(CH₂)₁₀₋₁₆—(O—C₂H₄)₁₋₂₅—OH: Octaethylene glycol monododecyl ether,Pentaethylene glycol monododecyl ether; Polyoxypropylene glycol alkylethers: CH₃—(CH₂)₁₀₋₁₆—(O—C₂H₆)₁₋₂₅—OH: Glcoside alkyl ethers:CH₃—(CH₂)₁₀₋₁₆—(O-Glucoside)₁₋₃—OH: Decyl glucoside, Lauryl glucoside,Octyl glucoside; Polyoxyethylene glycol octylphenol ethers:C₈H₁₇—(C₆H₄)—(O—C₂H₄)₁₋₂₅—OH: Triton X-100; Polyoxyethylene glycolalkyphenol ethers: C₉H₁₉—(C₆H₄)—(O—C₂H₄)₁₋₂₅—OH: Nonxynol-9; Glycerolalkyl esters: Glyceryl laurate Polyoxyethylene glycol sorbitn alkylesters: Polysorbates; Sorbitan alkyl esters: Spans; Cocamide MEA,cocamide DEA; Dodecyl dimethylamine oxide; Block copolymers ofpolyethylene glycol and polypropylene glycol: Poloxamers . . .

TABLE 1C Types of Carbohydrates General: Aldose • Ketose • Pyranose •Furanose Geometry Cyclohexane conformation • Anomer • MutarotationTrioses Ketotriose (Dihydroyacetone) Aldotriose (Glyceraldehyde)Tetroses Ketotetrose (Erythrulose) Ketopentose (Ribulose, Xylulose)Pentoses Aldopentose (Ribose, Arabinose, Xylose, Lyxose) MonosaccharidesDeoxy sugar (Deoxyribose) Ketohexose (Psicose, Fructose, Sorbose,Tagatose) Hexoses Aldohexose (Alose, Altrose, Glucose, Mannose, Gulose,Idose, Galactose, Talose) Deoxy sugar (Fucoe, Fuculose, Rhamnose) >6Heptose (Sedoheptulose) • Octose • Nonose (Neuraminic acid)Disaccharides Sucrose • Lactose • Maltose • Trehalose • Turanose •Cellobiose Trisaccharides Raffinose • Melezitose • MaltotrioseTetrasaccharides Acarbose • Stachyose Other oligosaccharidesFructooligosaccharide (FOS) • Galactooligosaccharides (GOS) • Mannan-oligosaccharides (MOS) Multiple Glucose/Glucan: Glycogen • Starch(Amylose, Amylopectin) • Cellulose • Dextrin/Dextran • Beta-glucan(Zymosan, Lentinan, Sizofiran) • Maltodextrin PolysaccharidesFructose/Fructan: Inulin • Levan beta 2-6 Mannose/MannanGalactose/alactan N-Acetylglucosemine: Chitin

The variations set forth in the foregoing description do not representall variations consistent with the subject matter described herein.Instead, they are merely some examples consistent with aspects relatedto the described subject matter. Wherever possible, the same referencenumbers will be used throughout the drawings to refer to the same orlike parts.

Although a few variations have been described in detail above, othermodifications or additions are possible. In particular, further featuresand/or variations can be provided in addition to those set forth herein.For example, the variations described above can be directed to variouscombinations and sub-combinations of the disclosed features and/orcombinations and sub-combinations of several further features disclosedabove. In addition, the logic flows and steps for use described hereindo not require the particular order shown, or sequential order, toachieve desirable results. Other variations can be within the scope ofthe claims.

1.-107. (canceled)
 108. A flowable formulation for use with atherapeutic device implanted to treat an eye, the formulationcomprising: a therapeutic agent having a molecular weight; and astabilizer to maintain stability of the therapeutic agent, wherein thestabilizer is selected based on the stabilizer comprising a molecularweight that is at least 10% of the molecular weight of the therapeuticagent, wherein the formulation is suitable for providing the therapeuticagent to an eye from within a therapeutic device implanted in the eye,the therapeutic device having a reservoir chamber and a porousstructure, wherein the stabilizer diffuses through the porous structureat a rate that leaves an amount of the stabilizer that is sufficient tostabilize for at least one month therapeutic agent remaining in thereservoir chamber.
 109. The formulation of claim 108, wherein thestabilizer comprises a molecular weight of at least 5 kilodaltons. 110.The formulation of claim 108, wherein the stabilizer comprises amolecular weight of at least 10 kilodaltons.
 111. The formulation ofclaim 108, wherein the therapeutic agent comprises a molecular weight ofat least 40 kilodaltons.
 112. The formulation of claim 108, wherein thetherapeutic agent comprises a Fab antibody fragment or a derivativethereof.
 113. The formulation of claim 112, wherein the therapeuticagent comprises ranibizumab.
 114. The formulation of claim 108, furthercomprising an amount of an erodible material to maintain the pH of thereservoir chamber at no more than 6.5 for an extended time of at leastone month.
 115. The formulation of claim 108, further comprising anamount of an erodible material to maintain the pH of the reservoirchamber at no more than 6.0 for an extended time of at least one month.116. The formulation of claim 108, further comprising particles to bindreversibly to the therapeutic agent, a majority of the particles havinga size greater than a size diffusible through the porous structure suchthat the majority of the particles remain in the reservoir chamber forthe extended time.
 117. The formulation of claim 108, wherein at least aportion of the stabilizer is encapsulated into particles of an erodiblematerial and the portion of the stabilizer remains in the device when afirst portion of the therapeutic agent is released so as to stabilize aremaining portion of the therapeutic agent in the reservoir chamber uponerosion of the particles.
 118. The formulation of claim 117, wherein theparticles of the erodible material comprises one or more of a suspensionor a slurry of the particles for injection into or exchange from thetherapeutic device.
 119. The formulation of claim 117, wherein theformulation comprises a pH of at least about 5.5 and the particles ofthe erodible material are capable of releasing about 1×10¹⁰ moles ofprotons per uL of formulation in the reservoir chamber so as to maintaina pH of the formulation below about 7 for an extended time of at leastabout one month.
 120. The formulation of claim 117, wherein the erodiblematerial is a polymer, the polymer comprising one or more of polylacticacid (PLA), polyglutamic acid (PGA), and PLA/PGA copolymer.
 121. Theformulation of claim 117, wherein the stabilizer modulates diffusion ofthe therapeutic agent and affects a release rate of the therapeuticagent from the therapeutic device when the therapeutic device isimplanted in the eye such that a portion of the stabilizer remains inthe reservoir chamber for the period of time when a first portion of thetherapeutic agent diffuses out of the reservoir chamber so as tostabilize a second portion of the therapeutic agent remaining in thereservoir chamber.
 122. The formulation of claim 108, wherein thereservoir chamber of the therapeutic device is non-permeable such thatmolecular diffusion of the therapeutic agent and the stabilizer from thereservoir chamber into the vitreous humor occurs only through the porousstructure.
 123. The formulation of claim 108, wherein the reservoirchamber is sized to hold the formulation and is refillable whileimplanted in the eye from outside the eye.